Linear polyester and semi-linear glycidol polymer systems: formulation and synthesis of novel monomers and macromolecular structures

ABSTRACT

Disclosed herein are glycidol-based polymers, nanoparticles, and methods related thereto useful for drug delivery. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is a Continuation of U.S. patent application Ser. No.13/919,916 (now U.S. Pat. No. 9,161,983), filed Jun. 17, 2013, whichclaims the benefit of U.S. Provisional Application No. 61/660,675 filedon Jun. 15, 2012; which applications are incorporated herein byreference in its entirety.

BACKGROUND

Many highly efficacious drugs have already been created and the mainhurdle that these drug molecules have to overcome is theirhydrophobicity. Due to this lack of solubility, regardless of the drugsefficacy, the molecules will never be cleared as viable treatmentoptions. Furthermore, biological therapeutics such as antibodies andproteins (e.g., growth factors) are not stable for a prolonged time inthe biological environment and impedes their activity and therapeuticefficacy. Moreover, it has been found that therapeutics can work veryefficiently together and enhance the therapeutic outcome known as thesynergistic effect.

Thus, there remains a need for delivery systems that addresshydrophobicity and/or lack of solubility. In view of the need ofdelivery systems that deliver drugs of different nature, can control thekinetics of the delivery, and react to external stimuli, multifaceteddelivery systems are being developed. The combinations of 3-Dnanoparticles are designed to deliver small molecules that are imbeddedin non-crosslinked or crosslinked matrices are of interest.Additionally, 2-D materials that contain no 3-D nanoparticle materialsare crosslinked to hydrophilic networks to be formed in click reactionsin hydrophilic and hydrophobic environments. The functionalities inthese hydrogel materials allow response to heat, reconfiguring thenetwork but not destroying the structure.

SUMMARY OF THE INVENTION

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates tocompounds that can be used in drug delivery, and composition thereof andmethods thereof.

Disclosed herein is a polymer comprising repeating units selected from:

wherein R⁰ is selected from H, alkyl, NH₂, and R¹; wherein R¹ comprisesa crosslinking functionality; wherein repeating units A1, A2, B1, and B2account for at least about 50 wgt % of the polymer; and wherein theratio of (A1+A2):(B1+B2) is greater than 1.

Also disclosed herein is a nanoparticle comprising the disclosedcompounds.

Also disclosed is a method for making a polymer, the method comprisingthe step of polymerizing glycidol in the presence of a tin catalyst.

Also disclosed herein is a method for forming a nanoparticle comprising:a. providing a polymer disclosed herein and crosslinking polymer withcrosslinks disclosed herein.

Also disclosed is a drug delivery method comprising the step ofadministering to a subject a composition comprising a polymer ornanoparticle disclosed herein, in combination with at least onepharmaceutically active agent and/or biologically active agent.

Also disclosed herein is a pharmaceutical composition comprising apolymer or nanoparticle disclosed herein; a pharmaceutically activeagent and/or biologically active agent; and a pharmaceuticallyacceptable carrier.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying Figures, which are incorporated in and constitute apart of this specification, illustrate several aspects and together withthe description serve to explain the principles of the invention.

FIG. 1 shows schematic representation of drug-loaded hyperbranchedpolyglycerols.

FIG. 2 shows a fluorescent image of polyglycerols loaded with atherapeutic cargo.

FIG. 3 shows a schematic representation of degradability of glycidolpolymers.

FIG. 4 shows schematic representations of glycidol polymers carryingsolubilized biological cargo.

FIG. 5 shows a schematic representation of a poly(ethyleneglycol)-protein conjugate.

FIG. 6 shows a schematic representation of a reaction scheme for theintroduction of allyl functionalities in the polymer systems of thepresent invention.

FIG. 7 shows the equation for degree of branching in the resultantpolymers with the variables referring to the integration values obtainedfrom quantitative ¹³CNMR investigation of the present invention.

FIG. 8 shows ¹³C-NMR spectra of glycidol homopolymer of the presentinvention.

FIG. 9 shows a table reporting experimental NMR data and degree ofbranching for polyglycidol systems of the present invention.

FIG. 10 shows a visual representation of depression of dendritic peakthrough kinetically controlled reactions of the present invention.

FIG. 11 shows a visual representation of poly(glycidol) branchingpossibilities.

FIG. 12 shows NMR spectra and a visual representation of poly(glycidol)branching possibilities.

FIG. 13 shows a schematic representation of ring opening possibilitiesfor polyglycidol systems.

FIG. 14 shows NMR spectra for glycidyl ester allyl of the presentinvention.

FIG. 15 shows NMR spectra for GLY/GEA polymer.

FIG. 16 shows a schematic representation of hydrophobicity of glycidolpolymers due to the presence of OPD.

FIG. 17 shows a schematic representation of a siRNA complexationreaction.

FIG. 18 shows a schematic representation of a dendritic polyglycerolswith an amine shell.

FIG. 19 shows a schematic representation of nanoparticle formationthrough a controlled thiolene-click reaction of the present invention.

FIG. 20 shows a schematic representation of formation of polyesternanoparticles.

FIG. 21 shows a schematic representation of thiolene-click GLY/AGEnanoparticle formation of the present invention.

FIG. 22 shows a schematic representation of loading of nanoparticle withsmall molecule drugs.

FIG. 23 shows a visual representation of the minimal size dispersity ofnanoparticle structures of the present invention.

FIG. 24 shows a transmission electron microscopy (TEM) image for GLY/AGEnanoparticles of the present invention.

FIG. 25 shows a transmission electron microscopy (TEM) image for GLY/AGEnanoparticles of the present invention.

FIG. 26 shows a transmission electron microscopy (TEM) image for GLY/AGEnanoparticles of the present invention.

FIG. 27 shows a schematic representation of an exemplary two componentdelivery system of the present invention.

FIG. 28 shows a schematic representation of exemplary reconfigurable andresponsive network systems of the present invention.

FIG. 29 shows a schematic representation of exemplary reaction schemesfor formation of network systems of the present invention.

FIG. 30 shows a visual representation of NMR spectra of an exemplaryglycidol polymer of the present invention.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

All publications mentioned herein are incorporated herein by referenceto disclose and describe the methods and/or materials in connection withwhich the publications are cited. The publications discussed herein areprovided solely for their disclosure prior to the filing date of thepresent application. Nothing herein is to be construed as an admissionthat the present invention is not entitled to antedate such publicationby virtue of prior invention. Further, the dates of publication providedherein can be different from the actual publication dates, which canrequire independent confirmation.

A. Definitions

As used herein, nomenclature for compounds, including organic compounds,can be given using common names, IUPAC, IUBMB, or CAS recommendationsfor nomenclature. When one or more stereochemical features are present,Cahn-Ingold-Prelog rules for stereochemistry can be employed todesignate stereochemical priority, E/Z specification, and the like. Oneof skill in the art can readily ascertain the structure of a compound ifgiven a name, either by systemic reduction of the compound structureusing naming conventions, or by commercially available software, such asCHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, a further aspect includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms a further aspect. It willbe further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or cannot occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the term “analog” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds.

As used herein, the term “subject” refers to the target ofadministration, e.g., an animal, such as a human. Thus the subject ofthe herein disclosed methods can be a vertebrate, such as a mammal, afish, a bird, a reptile, or an amphibian. Alternatively, the subject ofthe herein disclosed methods can be a human, non-human primate, horse,pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The termdoes not denote a particular age or sex. Thus, adult and newbornsubjects, as well as fetuses, whether male or female, are intended to becovered. In one aspect, the subject is a mammal. A patient refers to asubject afflicted with a disease or disorder. The term “patient”includes human and veterinary subjects. In some aspects of the disclosedmethods, the subject has been diagnosed with a need for treatment of oneor more muscle disorders prior to the administering step. In someaspects of the disclosed method, the subject has been diagnosed with aneed for increasing muscle mass prior to the administering step. In someaspects of the disclosed method, the subject has been diagnosed with aneed for increasing muscle mass prior to the administering step.

As used herein, the phrase “identified to be in need of treatment for adisorder,” or the like, refers to selection of a subject based upon needfor treatment of the disorder. For example, a subject can be identifiedas having a need for treatment of a disorder (e.g., a disorder relatedto cancer) based upon an earlier diagnosis by a person of skill andthereafter subjected to treatment for the disorder. It is contemplatedthat the identification can, in one aspect, be performed by a persondifferent from the person making the diagnosis. It is also contemplated,in a further aspect, that the administration can be performed by one whosubsequently performed the administration.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, sublingual administration, buccal administration, andparenteral administration, including injectable such as intravenousadministration, intra-arterial administration, intramuscularadministration, and subcutaneous administration. Administration can becontinuous or intermittent. In various aspects, a preparation can beadministered therapeutically; that is, administered to treat an existingdisease or condition. In further various aspects, a preparation can beadministered prophylactically; that is, administered for prevention of adisease or condition.

As used herein, the terms “effective amount” and “amount effective”refer to an amount that is sufficient to achieve the desired result orto have an effect on an undesired condition. For example, a“therapeutically effective amount” refers to an amount that issufficient to achieve the desired therapeutic result or to have aneffect on undesired symptoms, but is generally insufficient to causeadverse side effects. The specific therapeutically effective dose levelfor any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the specific composition employed; the age, body weight, general health,sex and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of a compound at levels lower than those required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved. If desired, the effective dailydose can be divided into multiple doses for purposes of administration.Consequently, single dose compositions can contain such amounts orsubmultiples thereof to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days. Guidance canbe found in the literature for appropriate dosages for given classes ofpharmaceutical products. In further various aspects, a preparation canbe administered in a “prophylactically effective amount”; that is, anamount effective for prevention of a disease or condition.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable, i.e., without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner.

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

A residue of a chemical species, as used in the specification andconcluding claims, refers to the moiety that is the resulting product ofthe chemical species in a particular reaction scheme or subsequentformulation or chemical product, regardless of whether the moiety isactually obtained from the chemical species. Thus, an ethylene glycolresidue in a polymer refers to one or more —OCH₂CH₂O— units in thepolter, regardless of whether ethylene glycol was used to prepare thepolter. Similarly, a sebacic acid residue in a polter refers to one ormore —CO(CH₂)₈CO— moieties in the polter, regardless of whether theresidue is obtained by reacting sebacic acid or an ester thereof toobtain the polymer. In certain aspects, a monomer residue in a polymercan also be described as a repeating unit.

As used herein, the term “biologically active agent” or “bioactiveagent” means an agent that is capable of providing a local or systemicbiological, physiological, or therapeutic effect in the biologicalsystem to which it is applied. For example, the bioactive agent can actto control infection or inflammation, enhance cell growth and tissueregeneration, control tumor growth, act as an analgesic, promoteanti-cell attachment, and enhance bone growth, among other functions.Other suitable bioactive agents can include anti-viral agents, vaccines,hormones, antibodies (including active antibody fragments sFv, Fv, andFab fragments), aptamers, peptide mimetics, functional nucleic acids,therapeutic proteins, peptides, or nucleic acids. Other bioactive agentsinclude prodrugs, which are agents that are not biologically active whenadministered but, upon administration to a subject are converted tobioactive agents through metabolism or some other mechanism.Additionally, any of the compositions of the invention can containcombinations of two or more bioactive agents. It is understood that abiologically active agent can be used in connection with administrationto various subjects, for example, to humans (i.e., medicaladministration) or to animals (i.e., veterinary administration).

As used herein, the term “pharmaceutically active agent” includes a“drug” or a “vaccine” and means a molecule, group of molecules, complexor substance administered to an organism for diagnostic, therapeutic,preventative medical, or veterinary purposes. This term includeexternally and internally administered topical, localized and systemichuman and animal pharmaceuticals, treatments, remedies, nutraceuticals,cosmeceuticals, biologicals, devices, diagnostics and contraceptives,including preparations useful in clinical and veterinary screening,prevention, prophylaxis, healing, wellness, detection, imaging,diagnosis, therapy, surgery, monitoring, cosmetics, prosthetics,forensics and the like. This term may also be used in reference toagriceutical, workplace, military, industrial and environmentaltherapeutics or remedies comprising selected molecules or selectednucleic acid sequences capable of recognizing cellular receptors,membrane receptors, hormone receptors, therapeutic receptors, microbes,viruses or selected targets comprising or capable of contacting plants,animals and/or humans. This term can also specifically include nucleicacids and compounds comprising nucleic acids that produce a bioactiveeffect, for example deoxyribonucleic acid (DNA) or ribonucleic acid(RNA). Pharmaceutically active agents include the herein disclosedcategories and specific examples. It is not intended that the categorybe limited by the specific examples. Those of ordinary skill in the artwill recognize also numerous other compounds that fall within thecategories and that are useful according to the invention. Examplesinclude a radiosensitizer, the combination of a radiosensitizer and achemotherapeutic, a steroid, a xanthine, a beta-2-agonistbronchodilator, an anti-inflammatory agent, an analgesic agent, acalcium antagonist, an angiotensin-converting enzyme inhibitors, abeta-blocker, a centrally active alpha-agonist, an alpha-1-antagonist,carbonic anhydrase inhibitors, prostaglandin analogs, a combination ofan alpha agonist and a beta blocker, a combination of a carbonicanhydrase inhibitor and a beta blocker, an anticholinergic/antispasmodicagent, a vasopressin analogue, an antiarrhythmic agent, anantiparkinsonian agent, an antiangina/antihypertensive agent, ananticoagulant agent, an antiplatelet agent, a sedative, an ansiolyticagent, a peptidic agent, a biopolymeric agent, an antineoplastic agent,a laxative, an antidiarrheal agent, an antimicrobial agent, anantifungal agent, or a vaccine. In a further aspect, thepharmaceutically active agent can be coumarin, albumin, bromolidine,steroids such as betamethasone, dexamethasone, methylprednisolone,prednisolone, prednisone, triamcinolone, budesonide, hydrocortisone, andpharmaceutically acceptable hydrocortisone derivatives; xanthines suchas theophylline and doxophylline; beta-2-agonist bronchodilators such assalbutamol, fenterol, clenbuterol, bambuterol, salmeterol, fenoterol;antiinflammatory agents, including antiasthmatic anti-inflammatoryagents, antiarthritis antiinflammatory agents, and non-steroidalantiinflammatory agents, examples of which include but are not limitedto sulfides, mesalamine, budesonide, salazopyrin, diclofenac,pharmaceutically acceptable diclofenac salts, nimesulide, naproxene,acetominophen, ibuprofen, ketoprofen and piroxicam; analgesic agentssuch as salicylates; calcium channel blockers such as nifedipine,amlodipine, and nicardipine; angiotensin-converting enzyme inhibitorssuch as captopril, benazepril hydrochloride, fosinopril sodium,trandolapril, ramipril, lisinopril, enalapril, quinapril hydrochloride,and moexipril hydrochloride; beta-blockers (i.e., beta adrenergicblocking agents) such as sotalol hydrochloride, timolol maleate, timolhemihydrate, levobunolol hydrochloride, esmolol hydrochloride,carteolol, propanolol hydrochloride, betaxolol hydrochloride, penbutololsulfate, metoprolol tartrate, metoprolol succinate, acebutololhydrochloride, atenolol, pindolol, and bisoprolol fumarate; centrallyactive alpha-2-agonists (i.e., alpha adrenergic receptor agonist) suchas clonidine, brimonidine tartrate, and apraclonidine hydrochloride;alpha-1-antagonists such as doxazosin and prazosin;anticholinergic/antispasmodic agents such as dicyclomine hydrochloride,scopolamine hydrobromide, glycopyrrolate, clidinium bromide, flavoxate,and oxybutynin; vasopressin analogues such as vasopressin anddesmopressin; prostaglandin analogs such as latanoprost, travoprost, andbimatoprost; cholinergics (i.e., acetylcholine receptor agonists) suchas pilocarpine hydrochloride and carbachol; glutamate receptor agonistssuch as the N-methyl D-aspartate receptor agonist memantine;anti-Vascular endothelial growth factor (VEGF) aptamers such aspegaptanib; anti-VEGF antibodies (including but not limited toanti-VEGF-A antibodies) such as ranibizumab and bevacizumab; carbonicanhydrase inhibitors such as methazolamide, brinzolamide, dorzolamidehydrochloride, and acetazolamide; antiarrhythmic agents such asquinidine, lidocaine, tocainide hydrochloride, mexiletine hydrochloride,digoxin, verapamil hydrochloride, propafenone hydrochloride, flecaimideacetate, procainamide hydrochloride, moricizine hydrochloride, anddiisopyramide phosphate; antiparkinsonian agents, such as dopamine,L-Dopa/Carbidopa, selegiline, dihydroergocryptine, pergolide, lisuride,apomorphine, and bromocryptine; antiangina agents and antihypertensiveagents such as isosorbide mononitrate, isosorbide dinitrate,propranolol, atenolol and verapamil; anticoagulant and antiplateletagents such as coumadin, warfarin, acetylsalicylic acid, andticlopidine; sedatives such as benzodiazapines and barbiturates;ansiolytic agents such as lorazepam, bromazepam, and diazepam; peptidicand biopolymeric agents such as calcitonin, leuprolide and other LHRHagonists, hirudin, cyclosporin, insulin, somatostatin, protirelin,interferon, desmopressin, somatotropin, thymopentin, pidotimod,erythropoietin, interleukins, melatonin, granulocyte/macrophage-CSF, andheparin; antineoplastic agents such as etoposide, etoposide phosphate,cyclophosphamide, methotrexate, 5-fluorouracil, vincristine,doxorubicin, cisplatin, hydroxyurea, leucovorin calcium, tamoxifen,flutamide, asparaginase, altretamine, mitotane, and procarbazinehydrochloride; laxatives such as senna concentrate, casanthranol,bisacodyl, and sodium picosulphate; antidiarrheal agents such asdifenoxine hydrochloride, loperamide hydrochloride, furazolidone,diphenoxylate hydrochloride, and microorganisms; vaccines such asbacterial and viral vaccines; antimicrobial agents such as penicillins,cephalosporins, and macrolides, antifungal agents such as imidazolic andtriazolic derivatives; and nucleic acids such as DNA sequences encodingfor biological proteins, and antisense oligonucleotides. It isunderstood that a pharmaceutically active agent can be used inconnection with administration to various subjects, for example, tohumans (i.e., medical administration) or to animals (i.e., veterinaryadministration).

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. It is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein asgeneric symbols to represent various specific substituents. Thesesymbols can be any substituent, not limited to those disclosed herein,and when they are defined to be certain substituents in one instance,they can, in another instance, be defined as some other substituents.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkylgroup can be cyclic or acyclic. The alkyl group can be branched orunbranched. The alkyl group can also be substituted or unsubstituted.For example, the alkyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether,halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.A “lower alkyl” group is an alkyl group containing from one to six(e.g., from one to four) carbon atoms.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” or “haloalkyl” specifically refers to analkyl group that is substituted with one or more halide, e.g., fluorine,chlorine, bromine, or iodine. The term “alkoxyalkyl” specifically refersto an alkyl group that is substituted with one or more alkoxy groups, asdescribed below. The term “alkylamino” specifically refers to an alkylgroup that is substituted with one or more amino groups, as describedbelow, and the like. When “alkyl” is used in one instance and a specificterm such as “alkylalcohol” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“alkylalcohol” and the like.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

The terms “amine” or “amino” as used herein are represented by theformula -NA¹A², where A¹ and A² can be, independently, hydrogen oralkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.The term “polter” as used herein is represented by the formula -(AO(O)C-A²-C(O)O)_(a)— or -(A¹O(O)C-A2-OC(O))_(a)—, where A¹ and A² canbe, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group described herein and “a” is aninteger from 1 to 500. “Polter” is as the term used to describe a groupthat is produced by the reaction between a compound having at least twocarboxylic acid groups with a compound having at least two hydroxylgroups.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein. The term “polyether” as used herein is represented by theformula -(A¹O-A²O)_(a)—, where A¹ and A² can be, independently, analkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group described herein and “a” is an integer of from 1 to500. Examples of polyether groups include polyethylene oxide,polypropylene oxide, and polybutylene oxide.

The term “azide” as used herein is represented by the formula —N₃.

The term “thiol” as used herein is represented by the formula —SH.

The terms “hydrolysable group” and “hydrolysable moiety” refer to afunctional group capable of undergoing hydrolysis, e.g., under basic oracidic conditions. Examples of hydrolysable residues include, withoutlimitation, acid halides, activated carboxylic acids, and variousprotecting groups known in the art (see, for example, “Protective Groupsin Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience,1999).

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

Certain materials, compounds, compositions, and components disclosedherein can be obtained commercially or readily synthesized usingtechniques generally known to those of skill in the art. For example,the starting materials and reagents used in preparing the disclosedcompounds and compositions are either available from commercialsuppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), AcrosOrganics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), orSigma (St. Louis, Mo.) or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wileyand Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition); and Larock'sComprehensive Organic Transformations (VCH Publishers Inc., 1989).

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds can not be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the invention. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of theinvention.

It is understood that the compositions disclosed herein have certainfunctions. Disclosed herein are certain structural requirements forperforming the disclosed functions, and it is understood that there area variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures willtypically achieve the same result.

B. Polymers

As briefly described herein, the present invention, in various aspects,relates to glycidol-based polymer systems. In a one aspect, as shownbelow, glycidol is an analog of ethylene glycol. In further aspects,glycidol can be ring opened in different ways, is capable of controlledpolymerization, and is inherently hydrophilic due to the presence of aprimary hydroxyl functionality. In one aspect, the glycidol polymers canbe semi-branched.

In a further aspect, the semi-branched architectures can be used fortransportation of drugs and other biological cargo, as shown in FIG. 1.However, this type of structure presents a number of limitations. Forexample, the vastly branched systems have limited post-modification, asthey only contain an assortment of primary and secondary hydroxylgroups, rather than an assortment of reactive points. In a still furtheraspect, the random configurations can lead to complications withintroducing the intended cargo to the system.

In further aspects, the glycidol based polymer systems comprise linearglycidols. In one aspect, linear glycidols can be accomplished usingglycidol derivatives and anionic polymerization methods, as representedby the reaction scheme below.

However, this method involves rigorous reaction conditions, is verysusceptible to oxygen, and requires numerous purification steps. In afurther aspect, this method does not deliver polymer systems with asuitable degradation profile. In a further aspect, the inherent watersolubility of poly(glycidol) systems can be utilized to allow a methodthat will provide more linear poly(glycidol) systems.

In a further aspect, the linear glycidols comprise additional functionalgroup containing co-monomers. In a still further aspect, the additionalfunctional groups can be subsequently cross-linked to form nanoparticlestructures. These nanoparticles will imbibe the applicability of thewater-soluble glycidol units with the functionality of groups, such asallyl's and epoxides, which are capable of a range of post-modificationreactions. In a further aspect, this will allow for the encapsulation ofdrug molecules followed by the addition of targeting units and/or dyes,as depicted in FIG. 2. In a still further aspect, the addition of thisincreased functionality provides a variety of nanoparticles that can betailored to specific needs, as well as structures whose functionalitycan be verified in a laboratory setting. In an even further aspect, thepolymer systems can comprise polyester nanoparticle systems for thetransport of hydrophobic drug molecules.

As described above, glycidol's analogous structure to polyethyleneglycol, as well as its abundance of primary and secondary hydroxylgroups provides a system that is relatively non-toxic and exceedinglyhydrophilic. In various aspects, glycidol-based systems involve theformation of single-step dendrimer like macromolecules that provide theabilities of dendrimers without the painstaking process of dendrimergrowth.[2, 4, 5, 18-22] In a further aspect, glycidol's success relatesto its latent AB₂ monomer type. Thus, in a still further aspect, theglycidol monomer does not become a true AB₂ type monomer until it hasundergone ring opening. In various further aspects, this characteristicallows for additional control through a ring-opening polymerizationrather than a rampant polycondensation, which is the usual reaction typeused with other AB₂ type monomers.[4, 23, 24]

In a further aspect, the added control allows for investigation ofbranched polyglycidols and the factors that lead to branching. In astill further aspect, implementation of the ring-opening polymerization(ROP) mechanism can yield materials that are more chemically guidedrather than empirical in the degree of branching. In an even furtheraspect, hyperbranched polyglycidol systems can be formed in varyingsizes, with low polydispersity indices (PDIs) and controlled degrees ofpolymerization (DP). In a still further aspect, these polymer systemscan be advantageous as alternatives to multistep dendrimer species.[2,4, 18-20, 22, 25]

In various aspects. the polymer systems formed from these methods haveuse in numerous applications ranging from potential vaccine models[26]and selective drug delivery vehicles[11-14, 27], to biomineralizationcontrol and soluble catalyst supports in organic synthesis. In a furtheraspect, much of the success seen in these applications relates to theinherent characteristics of the polyglycerol's branched structure. In astill further aspect, limiting the degree of branching (DB), preferablywith little change to the PDI, can be beneficial in the formation ofnew, and possibly more robust, poly(glycidol) architectures.

As briefly described, the current methods for the formation ofcompletely linear poly(glycidol) polymers rely on the use of protectedglycidol derivatives polymerized under stringent anionic polymerizationconditions. In a further aspect, the polymer then undergoes adeprotection step that removes the protecting group, leaving a linearpoly(glycidol) structure. While an effective method for the formation oflinear poly(glycidol) species, this method does not address the problemsof the system.[28-31]

In some aspects, glycidol based polymers, much like polyethylene glycol(PEG), have severely slow degradation profiles. While not a significantproblem for low molecular weight species, the large macromolecularhyperbranched systems cannot be easily eliminated from the body. In afurther aspect, the difficult of elimination from the body equates to aninevitable buildup of poly(glycidol) (PG) over time and one would expecteventual data will show higher toxicity with this build up, as is beingseen now with PEG. In a still further aspect, the presence of only onepost modification unit, the hydroxyl side arms, adds an extra challengeto the creation of a polymer structure that has a variety ofpost-modification capabilities.

In various further aspects, the present polyglycidol polymer systems canbe useful in the solubilization of proteins and siRNA, whichinvestigations had thus far been dominated by polyacrylates having PEGside chains.[32, 33] In most aspects, RAFT initiators are attached tothiol groups on the periphery of the structures, and PEG is grown tocover the outside and increase hydrophilicity.[34] Traditional methodsare not ideal because they severely diminish the activity of the proteinas well as introduces high molecular weight linear PEG into the body,which cannot easily be eliminated.[35] It is this method of proteinsolubilization that has been the cause of recent PEG toxicity problems.In some aspects, the attachment of branched PEG systems tothiol-modified siRNA and has shown an increase in biological half-lifedue to reduced immunogenicity, arising from the morphology of thebranched structure, and enhanced resistance against proteolysis.[33]

In further aspects, poly(glycidol) can be used as a method of increasingthe solubility of biological structures, as depicted in FIG. 3. In astill further aspect, the ability to control the degree of branchingpresent will be integral to the efficacy of the synthesized structuresand will allow for a more tailored approach to solubilization ofbiological structures and their behavior in vivo, as shown in FIGS. 4and 5. In a yet further aspect, facilitated by the increaseddegradability, the glycidol based copolymers can be both more effectiveand less harmful than their PEG counterparts.

Although a seemingly glaring problem, the low degree of solubility inthe polyglycerol systems has, for the most part, been overlooked. Ratherthan attempting to form polyglycerols with increased capabilities, alarge amount of research has been aimed at increasing the hydrophilicityof polyester structures. Using polyether macroinitiators in the attemptto form block copolymers is one method of combating this downfall of thepolyester systems. Unfortunately, the polymers synthesized in thismanner are highly prone to the formation of micellular structures, thusdrastically diminishing their actual viability.[1] Few studies have beenattempted on the basis of random copolymerization of glycidol with othermonomer species, and rarely address the branching characteristics of thesynthesized polymers.[24, 36] These copolymerizations have also beendictated by the use of a single catalyst, stannous ethylhexanoate, whichis a common lactide polymerization catalyst that implements acoordination-insertion type mechanism.

The compounds and compositions described herein combat the problemsassociated with polyglycerols, while still maintaining a high degree ofwater solubility and low PDI values. In a further aspect, the presentdisclosure provides inclusion of increased physiological degradability,through the incorporation of esters, as well as the introduction of moreviable post modification units, by the addition of allyl groups. In afurther aspect, the implementation of stannous triflate has been chosenas the desired catalysis method based on its ability to allow for lowreaction temperatures while maintaining high polymerization rates andlow PDI values.

In a still further aspect, by employing the stannous triflate catalystat low temperatures, the DB of the resulting polymers can be restrictedto well below the currently published values of 40% and higher. In stillfurther aspect, the present invention can comprise a range ofcomonomers, both commercially available and novel, which exhibit theability to copolymerize with glycidol to form an array of new andexciting polymer architectures. In a yet further aspect, the polymerscomprise desirable structural features and can provide new polymers withcustomizable degrees of branching, high functionality, increasedsolubility, and tunable biodegradability, thus imbuing all the benefitsof polyglycerols to systems that are more tailored for delivery of arange of drugs and biological cargo. In an even further aspect, thechemical characteristics of the synthesized polymers were investigatedthrough both ¹HNMR and ¹³CNMR techniques, and are further described inthe Examples.

Disclosed herein is a polymer comprising repeating units selected from:

wherein R⁰ is selected from H, alkyl, NH₂, and R¹; wherein R¹ comprisesa crosslinking functionality; wherein repeating units A1, A2, B1, and B2account for at least about 50 wgt % of the polymer; and wherein theratio of (A1+A2):(B1+B2) is greater than 1.

In one aspect, the ratio of (A1+A2):(B1+B2) is greater than 1. Inanother aspect, the ratio of (A1+A2):(B1+B2) is greater than 3. In yetanother aspect, the ratio of (A1+A2):(B1+B2) is greater than 5. In yetanother aspect, the ratio of (A1+A2):(B1+B2) is greater than 10. In yetanother aspect, the ratio of (A1+A2):(B1+B2) is greater than 25. In yetanother aspect, the ratio of (A1+A2):(B+B2) is greater than 50. In yetanother aspect, the ratio of (A1+A2):(B1+B2) is greater than 100. In yetanother aspect, the ratio of (A1+A2):(B1+B2) is from 1 to 100. In yetanother aspect, the ratio of (A1+A2):(B1+B2) is from 5 to 100. In yetanother aspect, the ratio of (A1+A2):(B1+B2) is from 10 to 100. In yetanother aspect, the ratio of (A1+A2):(B1+B2) is from 25 to 100.

In one aspect, repeating units A¹; A2; B1; and B2 account for at leastabout 50 wgt % of the polymer. In another aspect, repeating units A1;A2; B1; and B2 account for at least about 60 wgt % of the polymer. Inyet another aspect, repeating units A1; A2; B1; and B2 account for atleast about 60 wgt % of the polymer. In yet another aspect, repeatingunits A1; A2; B1; and B2 account for at least about 70 wgt % of thepolymer. In yet another aspect, repeating units A1; A2; B1; and B2account for at least about 80 wgt % of the polymer. In yet anotheraspect, repeating units A1; A2; B1; and B2 account for at least about 90wgt % of the polymer. In yet another aspect, repeating units A1; A2; B1;and B2 account for at least about 95 wgt % of the polymer. In yetanother aspect, repeating units A1; A2; B1; and B2 account for at leastabout 99 wgt % of the polymer.

In one aspect, the polymer is covalently bonded to a biologic agent,such as a protein, DNA, or SiRNA, for example, a protein. Such systemcan enhance the solubility of the biologic agent.

In one aspect, the polymer comprising at least one repeating unit formedfrom a monomer selected from:

or a combination thereof.

In one aspect, the polymer comprises at least one repeating unit from amonomer selected from:

or a combination thereof,and wherein the polymer is oxidized to form repeating units comprisingepoxides or alkynes.

It is understood that all or only a portion of the repeating units areoxidized in the polymer. Thus, it is understood that the resultantpolymer can comprise repeating units comprising alkenes and repeatingunits comprising epoxides and/or alkynes. For example, the polymer cancomprise at least 1%, 5%, 10%, 15%, 20%, or 25% repeating units thathave been oxidized. Thus, in one aspect, the polymer comprises repeatingunits comprising pendent groups selected from

or a combination thereof.

In one aspect, the polymer further comprises a repeating unit formedfrom

In another aspect, the polymer further comprises a repeating unit formedfrom

In yet another aspect, the polymer further comprises a repeating unitformed from

In yet another aspect, the polymer further comprises a repeating unitformed from

In yet another aspect, the polymer further comprises a repeating unitformed from

In yet another aspect, the polymer further comprises a repeating unitformed from

In yet another aspect, the polymer further comprises a repeating unitformed from

In yet another aspect, the polymer further comprises a repeating unitformed from

In yet another aspect, the polymer further comprises a repeating unitformed from

In yet another aspect, the polymer further comprises a repeating unitformed from

In yet another aspect, the polymer further comprises a repeating unitformed from

In yet another aspect, the polymer further comprises a repeating unitformed from

In yet another aspect, the polymer further comprises a repeating unitformed from

In one aspect, the polymer further comprises crosslinks, wherein thecrosslinks comprise

wherein at least one of

is not 0.

The crosslinks binds two or more polymers together. The polymers can beany polymer disclosed herein. The crosslinks can comprise one or more,such as two, moieties that can react with one or more of the disclosedpolymers thereby linking the polymers together. Thus, suitable moietiesinclude those that can react with alkenes, epoxides, or alkynes.Non-limiting moieties include —SH, —NH₂, and

The resultant polymer will then comprise one or more bonds which is aresult from these reactions. For example, the polymer can comprise —S—and —NH— bonds. It is also understood that these reactions will reducethe alkenes, alkynes, or epoxides that participates in the reactions.

In one aspect, the polymer comprises

Accordingly, the polymer can comprise the structure

wherein Z¹ is

wherein Z² is

wherein Z³ is

wherein Z⁴ is

wherein Z⁵ is

or a combination thereof;wherein, simultaneously, X₁ is from greater than 0% to 90%, X₂ is from0% to 95%, X₃ is from 0% to 90%, X₄ is from 0% to 90%, and X₅ is fromgreater than 0% to 90%, provided that X₁+X₂+X₃+X₄+X₅ equals 100%; andwherein each R¹ independently comprises a crosslinking functionality

In one aspect, the crosslinking functionality comprises an allyl,epoxide, amine, thiol, azide, or alkyne functionality. In one aspect,the crosslinking functionality comprises an allyl functionality. Inanother aspect, the crosslinking functionality comprises an epoxide. Inyet another aspect, the crosslinking functionality comprises an aminefunctionality. In yet another aspect, the crosslinking functionalitycomprises a thiol functionality. In yet another aspect, the crosslinkingfunctionality comprises an azide functionality. In yet another aspect,the crosslinking functionality comprises an alkyne functionality.

In one aspect, polymer has the structure selected from the groupconsisting of

In one aspect, the polymer can comprise one or more of repeating unitsselected from:

or a combination thereof.

In another aspect, the polymer can comprise the structure

wherein each Z¹ independently is

wherein each Z² independently is

wherein Z³ is

wherein Z⁴ is

wherein each Z⁶ independently comprises

and optionally independently comprises

or a combination thereof; wherein, simultaneously, X₁ is from greaterthan 0% to 90%, X₂ is from 0% to 95%, X₃ is from 0% to 90%, X₄ is from0% to 90%, and X₆ is from greater than 0% to 90%, provided thatX₁+X₂+X₃+X₄+X₆ equals 100%; wherein each R¹ independently comprises acrosslinking functionality; and wherein L¹ comprises

wherein least one of

is not 0.

In one aspect, the compound comprises the structure

In one aspect, the polymer comprises a structure formed from reacting apolymer disclosed herein further comprising repeating units

with a polymer comprising at least one repeating unit formed from

In one aspect, such polymer further comprises a structure formed fromreacting the polymer with a polymer comprising at least one repeatingunit formed from or

Also disclosed herein is a composition comprising a. a polymercomprising repeating units formed from monomers

wherein the polymer is crosslinked via crosslinks, wherein thecrosslinks comprises

wherein at least one

is not 0; and b. a polymer comprising repeating units selected from:

wherein R⁰ is selected from H, alkyl, NH₂, or R¹; wherein R¹ comprises acrosslinking functionality; wherein repeating units A1; A2; B1; and B2account for at least about 50 wgt % of the polymer; and wherein theratio of (A1+A2):(B1+B2) is greater than 1, wherein the polymers areoptionally covalently bonded together.

Thus, the polymer can comprise the structure

wherein L² comprises

wherein at least one of

is not 0; andwherein each of x₇, x₈, x₉, and x₁₀ independently are 1 to 1000. Thepolyglycidol is reversibly attached and disconnected throughtransesterification reactions. The attachment of the polyglycidol to thepolycarbonate via a transesterification reaction can be promoted by theuse of zinc acetate and heat. Such reaction is reversible. Theattachment and disconnection of the polyglycidol can be a function ofthe temperature, thus, the structure of the compound can be controlledby altering the temperature. Such compound is called a macroscopicnetwork and can be thermally responsive. Thus, the properties of thecompound can be altered by attaching or disconnecting the polyglycidolto the polycarbonate polymer. A therapeutic agent, diagnostic agent, orprophylactic agent, or a mixture thereof, can be present in acomposition comprising the compound or macroscopic network. Thesemacroscopic networks can be altered via reversible trans-esterificationreactions, thereby changing the properties of the macroscopic network.An example of such technology is described by Montarnal et al. (Science,334, 965 (2011), which is hereby incorporated by references in itsentirety.

In one aspect, the polymer is a macroscopic network.

In one aspect, the polymer is biodegradable.

In one aspect, the polymer has a weight average molecular weight from 1kDa to 1,000 kDa. In another aspect, the polymer has a weight averagemolecular weight from 1 kDa to 500 kDa. In yet another aspect, thepolymer has a weight average molecular weight from 1 kDa to 150 kDa. Inyet another aspect, the polymer has a weight average molecular weightfrom 1 kDa to 100 kDa. In yet another aspect, the polymer has a weightaverage molecular weight from 1 kDa to 75 kDa. In yet another aspect,the polymer has a weight average molecular weight from 1 kDa to 50 kDa.In yet another aspect, the polymer has a weight average molecular weightfrom 1 kDa to 25 kDa. In yet another aspect, the polymer has a weightaverage molecular weight from 1 kDa to 10 kDa.

In one aspect, the polymer has a PDI from 1.01 to 5.0. In anotheraspect, the polymer has a PDI from 1.01 to 4.0. In yet another aspect,the polymer has a PDI from 1.01 to 3.0. In yet another aspect, thepolymer has a PDI from 1.01 to 2.0. In yet another aspect, the polymerhas a PDI from 1.01 to 1.5. In yet another aspect, the polymer has a PDIfrom 1.01 to 1.25. In yet another aspect, the polymer has a PDI from1.01 to 1.10.

a. X Groups

In one aspect, X₁+X₂ equals from 50% to 99%. In another aspect, X₁+X₂equals from 60% to 95%. In yet another aspect, X₁+X₂ equals from 70% to90%.

In one aspect, X₁+X₂+X₃+X₄ equals from 50% to 99%. In another aspect,X₁+X₂+X₃+X₄ equals from 60% to 95%. In yet another aspect X₁+X₂+X₃+X₄equals from 70% to 90%.

In one aspect, X_(5s) is from 1% to 40%. In another aspect, X₅ is from5% to 35%. In yet another aspect, X₅ is from 10% to 30%.

In one aspect, X₂, X₃, and X₄ are 0%. In another aspect, X₂ is greaterthan 0% to 90% and X₃, and X₄ are 0%. In yet another aspect, X₂, X₃, andX₄ are from greater than 0% to 90%.

In one aspect, each of X₁, X₂, X₃, X₄, and X₅ independently are 1 to1000. In one aspect, each of X₁, X₂, and X₅ independently are 1 to 1000.In one aspect, each of X₁ and X₅ independently are 1 to 1000. In anotheraspect, each of X₁, X₂, X₃, X₄, and X₅ independently are 1 to 500. Inyet another aspect, each of X₁, X₂, X₃, X₄, and X₅ independently are 1to 300. In yet another aspect, each of X₁, X₂, X₃, X₄, and X₅independently are 1 to 100. In yet another aspect, each of X₁, X₂, X₃,X₄, and X₅ independently are 1 to 50. In yet another aspect, each of X₁,X₂, X₃, X₄, and X₅ independently are 1 to 25. In another aspect, each ofX₁, X₂, and X₅ independently are 1 to 500. In yet another aspect, eachof X₁, X₂, and X₅ independently are 1 to 300. In yet another aspect,each of X₁, X₂, and X₅ independently are 1 to 100. In yet anotheraspect, each of X₁, X₂, and X₅ independently are 1 to 50. In yet anotheraspect, each of X₁, X₂, and X₅ independently are 1 to 25. In anotheraspect, each of X₁ and X₅ independently are 1 to 500. In yet anotheraspect, each of X₁ and X₅ independently are 1 to 300. In yet anotheraspect, each of X₁ and X₅ independently are 1 to 100. In yet anotheraspect, each of X₁ and X₅ independently are 1 to 50. In yet anotheraspect, each of X₁ and X₅ independently are 1 to 25.

In one aspect, each of X₁, X₂, X₃, X₄, and X₆ independently are 1 to1000. In one aspect, each of X₁, X₂, and X₆ independently are 1 to 1000.In one aspect, each of X₁ and X₆ independently are 1 to 1000. In anotheraspect, each of X₁, X₂, X₃, X₄, and X₆ independently are 1 to 500. Inyet another aspect, each of X₁, X₂, X₃, X₄, and X₆ independently are 1to 300. In yet another aspect, each of X₁, X₂, X₃, X₄, and X₆independently are 1 to 100. In yet another aspect, each of X₁, X₂, X₃,X₄, and X₆ independently are 1 to 50. In yet another aspect, each of X₁,X₂, X₃, X₄, and X₆ independently are 1 to 25. In another aspect, each ofX₁, X₂, and X₆ independently are 1 to 500. In yet another aspect, eachof X₁, X₂, and X₆ independently are 1 to 300. In yet another aspect,each of X₁, X₂, and X₆ independently are 1 to 100. In yet anotheraspect, each of X₁, X₂, and X₆ independently are 1 to 50. In yet anotheraspect, each of X₁, X₂, and X₆ independently are 1 to 25. In anotheraspect, each of X₁ and X₆ independently are 1 to 500. In yet anotheraspect, each of X₁ and X₆ independently are 1 to 300. In yet anotheraspect, each of X₁ and X₆ independently are 1 to 100. In yet anotheraspect, each of X₁ and X₆ independently are 1 to 50. In yet anotheraspect, each of X₁ and X₆ independently are 1 to 25.

In one aspect, each of x₇, x₈, x₉, and x₁₀ independently are 1 to 1000.In another aspect, each of X₇, x₈, x₉, and x₁₀ independently are 1 to500. In yet another aspect, each of x₇, x₈, x₉, and x₁₀ independentlyare 1 to 300. In yet another aspect, each of x₇, x₈, x₉, and x₁₀independently are 1 to 100. In yet another aspect, each of X₇, x₈, x₉,and x₁₀ independently are 1 to 50. In yet another aspect, each of x₇,x₈, x₉, and x₁₀ independently are 1 to 25.

b. Z Groups

It is understood that the Z groups represent It is understood that thearrangement of Z groups in the polymers disclosed herein can be in anyorder, for example, Z¹, Z², Z³, Z⁴, and Z⁵ can be in any order. Thus, itis also understood that the polymer can be a random copolymer, wherebythe order of each repeat unit of Z¹, Z², Z³, Z⁴, and Z⁵ is random.

In one aspect, Z¹ is

In another aspect, Z¹ is

In yet another aspect, Z¹ is

In yet another aspect, Z¹ is

In one aspect, Z² is

In another aspect, Z² is

In one aspect, Z⁵ is

In another aspect, Z⁵ is

In yet another aspect, Z⁵ is

In yet another aspect, Z⁵ is

In yet another aspect, Z⁵ is

In yet another aspect, Z⁵ is

In yet another aspect, Z⁵ is

In one aspect, each Z⁶ comprises

In another aspect, each Z⁶ comprises

In one aspect, Z¹¹ is

In one aspect, Z¹² is

In one aspect, Z¹³ is

c. R Groups

In one aspect, R⁰ is H. In another aspect, R⁰ is alkyl. In yet anotheraspect, R⁰ is NH₂. In yet another aspect, R⁰ is R¹.

In one aspect, each of R¹ and R² independently comprises

wherein at least one of

is not 0.

In one aspect, R¹ comprises

for example, R¹ can comprise

In one aspect, R¹ comprises

In another aspect, R¹ comprises

In one aspect, R¹ comprise

In yet another aspect, R¹ comprises

In yet another aspect, R¹ comprises

and an allyl functionality.

In one aspect, R² comprises

for example, R² can comprise

In one aspect, R² comprises

In another aspect, R² comprises

In one aspect, R² comprises

In yet another aspect, R² comprises

In yet another aspect, R¹ comprises

and an allyl functionality.

In one aspect, the each of R¹ and R² independently are selected from thegroup consisting of

In one aspect, R¹ is

In another aspect, R¹ is

In yet another aspect, R¹ is

In yet another aspect, R¹ is

In yet another aspect, R¹ is

In yet another aspect, R¹ is

In yet another aspect, R¹ is

In yet another aspect, R¹ is

In yet another aspect, R¹ is

In yet another aspect, R¹ is

In yet another aspect, R¹ is

In one aspect, R² is

In another aspect, R² is

In yet another aspect, R² is

In yet another aspect, R² is

In yet another aspect, R² is

In yet another aspect, R² is

In yet another aspect, R² is

d. Crosslinks and L Groups

In one aspect, crosslinks or L¹ comprises

wherein least one of

is not 0.

In one aspect, crosslinks or L¹ comprises at least

In one aspect, L¹ comprises at least

In one aspect, crosslinks or L¹ comprises one or more of

or any combination thereof.

In one aspect, crosslinks or L¹ comprises one or more of

In another aspect, crosslinks or L¹ comprises one or more of

In yet another aspect, crosslinks or L¹ comprises one or more of

In yet another aspect, crosslinks or L¹ comprises one or more of

In yet another aspect, crosslinks or L¹ comprises one or more of

In one aspect, L¹ comprises one or more of

or any combination thereof.

In one aspect, L¹ comprises two of

or any combination thereof.

In another aspect, L¹ comprises two of

or any combination thereof.

In one aspect, L¹ is

In one aspect, L² comprises

wherein at least one of

is not 0.

In one aspect, L² comprises at least

In one aspect, L² comprises at least

In one aspect, L² comprises

or any combination thereof.

In a further aspect, the invention relates to a polyglycidol having adegree of branching of less than about 0.25. For example, the degree ofbranching can less than about 0.20, less than about 0.15, or less thanabout 0.10.

C. Nanoparticles

Also disclosed herein is a nanoparticle comprising one or more compoundsor polymers disclosed herein. In one aspect, the nanoparticle is madefrom one or more compounds or polymers disclosed herein, for example,the nanoparticle is made from one or more polymers disclosed herein. Inone aspect, the nanoparticle comprises crosslinked polymers disclosedherein.

In one aspect, the nanoparticle further comprises at least onepharmaceutically active agent and/or biologically active agent.

In one aspect, the nanoparticle is biodegradable. The biodegradabilitycan depend on the number of hydrolysable bonds, such as ester bonds,present in the compounds making up the nanoparticle.

In one aspect, the nanoparticle is hydrophilic. In another aspect, the tat least one pharmaceutically active agent and/or biologically activeagent is hydrophobic. In another aspect, the at least onepharmaceutically active agent and/or biologically active agent is aprotein, DNA, or SiRNA. In one aspect, the at least one pharmaceuticallyactive agent and/or biologically active agent is covalently bonded tothe nanoparticle.

In one aspect, the nanoparticle is between 1 nm and 1000 nm in diameter.In another aspect, the nanoparticle is between 1 nm and 750 nm indiameter. In yet another aspect, the nanoparticle is between 1 nm and500 nm in diameter. In yet another aspect, the nanoparticle is between 1nm and 250 nm in diameter. In yet another aspect, the nanoparticle isbetween 1 nm and 100 nm in diameter.

In one aspect, the nanoparticle comprises reactive functionalities, suchas a hydroxyl group, an amine group, a thiol group, an allyl group, anepoxide, or an alkyne group, or a combination thereof.

D. Compositions and Pharmaceutical Compositions

Also disclosed herein are compositions, such as pharmaceuticalcompositions.

In one aspect, the pharmaceutical composition comprises a) a compound orpolymer disclosed herein; b) pharmaceutically active agent and/orbiologically active agent; and c) a pharmaceutically acceptable carrier.

In one aspect, the pharmaceutical composition comprises a) ananoparticle disclosed herein; b) pharmaceutically active agent and/orbiologically active agent; and c) a pharmaceutically acceptable carrier.

In one aspect, the invention relates to pharmaceutical compositionscomprising the disclosed compounds and/or nanoparticles;pharmaceutically active agent and/or biologically active agent, and apharmaceutically acceptable carrier or salt thereof. In an aspect, thedisclosed pharmaceutical compositions can be provided comprising atherapeutically effective amount of the therapeutic agent, diagnosticagent, or prophylactic agent, or a mixture thereof, and apharmaceutically acceptable carrier. The disclosed pharmaceuticalcompositions can be provided comprising a prophylactically effectiveamount of the therapeutic agent, diagnostic agent, or prophylacticagent, or a mixture thereof, and pharmaceutically acceptable carrier.

In one aspect, the pharmaceutical composition comprises one or morepharmaceutically active agent and/or biologically active agents. Thecompounds and nanoparticles disclosed herein are capable of being loadedwith several different classes of therapeutics. Thus, the pharmaceuticalcomposition is capable of delivering at least two different classes oftherapeutics. For example, the therapeutic agent can comprise a MEKinhibitor and a bone morphogenetic protein 2 (BMP2) growth factor. Inone aspect, the therapeutic agent is hydrophobic. The compounds andnanoparticles are capable of being a delivery vehicle for therapeuticagents, diagnostic agents, or prophylactic agents that were previouslydifficult to deliver due to their physical properties, such as theirhydrophobicity. In one aspect, an effective amount of a therapeuticagent, diagnostic agent, or prophylactic agent can be present in thepharmaceutical composition. For example, an effective amount of atherapeutic agent, diagnostic agent, or prophylactic agent can be loadedin the compounds or nanoparticles disclosed herein.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likecan be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like can be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets can be coated by standard aqueous or nonaqueoustechniques

The instant compositions include compositions suitable for oral, rectal,topical, and parenteral (including subcutaneous, intramuscular, andintravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions can be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable forparenteral administration can be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, mouth washes, gargles, and the like.Further, the compositions can be in a form suitable for use intransdermal devices. These formulations can be prepared, utilizing acompound of the invention, or pharmaceutically acceptable salts thereof,via conventional processing methods. As an example, a cream or ointmentis prepared by mixing hydrophilic material and water, together withabout 5 wt % to about 10 wt % of the compound, to produce a cream orointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories can be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above can include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound of the invention, and/or pharmaceuticallyacceptable salts thereof, can also be prepared in powder or liquidconcentrate form.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors. Such factorsinclude the age, body weight, general health, sex, and diet of thepatient. Other factors include the time and route of administration,rate of excretion, drug combination, and the type and severity of theparticular disease undergoing therapy.

The present invention is further directed to a method for themanufacture of a medicament for treatment of a disorder in a subject(e.g., humans) comprising combining one or more disclosed compounds,products, or compositions with a pharmaceutically acceptable carrier ordiluent. Thus, in one aspect, the invention relates to a method formanufacturing a medicament comprising combining at least one disclosedcompound, a therapeutic agent, diagnostic agent, or prophylactic agent,or a mixture thereof, with a pharmaceutically acceptable carrier ordiluent.

It is understood that the disclosed compositions can be prepared fromthe disclosed compounds. It is also understood that the disclosedcompositions can be employed in the disclosed methods of using.

A. Methods of Using the Pharmaceutical Compositions

Disclosed herein is a drug delivery method comprising the step ofadministering to a subject a composition comprising a polymer ornanoparticle disclosed herein, in combination with at least onepharmaceutically active agent and/or biologically active agent. In oneaspect, the composition further comprises a pharmaceutically acceptablecarrier. In one aspect, the method comprises administering an effectiveamount of the pharmaceutically active agent and/or biologically activeagent to the subject. In one aspect, the effective amount is atherapeutically effective amount. Such amount can be determined by oneskilled in the art.

In one aspect, the therapeutic agent is a cancer agent. In anotheraspect, the therapeutic agent is a protein, DNA, or SiRNA.

In one aspect, the subject is an animal. In a further aspect, thesubject is a mammal. In a yet further aspect, the subject is a primate.In a still further aspect, the subject is a human. In an even furtheraspect, the subject is a patient.

In a further aspect, the pharmaceutical composition is administeredfollowing identification of the subject in need of treatment ofdisorder. In a still further aspect, the pharmaceutical composition isadministered following identification of the subject in need ofprevention of a disorder. In an even further aspect, the subject hasbeen diagnosed with a need for treatment of a disorder prior to theadministering step.

In one aspect, the method delivers one or more therapeutic agents. Thecompounds and nanoparticles disclosed herein are capable of being loadedwith several different classes of therapeutics. Thus, the method iscapable of delivering at least two different classes of therapeutics.For example, the therapeutic agent can comprise a MEK inhibitor and abone morphogenetic protein 2 (BMP2) growth factor.

In one aspect, the method comprises administering an effective amount ofthe pharmaceutically active agent and/or biologically active agent tothe subject. In one aspect, the effective amount is a therapeuticallyeffective amount. Such amount can be determined by one skilled in theart.

In one aspect, the therapeutic agent is a cancer agent. In anotheraspect, the pharmaceutically active agent and/or biologically activeagent is a protein, DNA, or SiRNA.

In one aspect, the subject is an animal. In a further aspect, thesubject is a mammal. In a yet further aspect, the subject is a primate.In a still further aspect, the subject is a human. In an even furtheraspect, the subject is a patient.

In a further aspect, the pharmaceutical composition is administeredfollowing identification of the subject in need of treatment ofdisorder. In a still further aspect, the pharmaceutical composition isadministered following identification of the subject in need ofprevention of a disorder. In an even further aspect, the subject hasbeen diagnosed with a need for treatment of a disorder prior to theadministering step.

E. Method of Making Polymers

Also disclosed here is a method of making a polymer, the methodcomprising the step of polymerizing glycidol in the presence of a tincatalyst. In one aspect, the tin catalyst is a tin(II) catalyst, forexample, Sn(OTf)₂.

Also disclosed is a polymer made from the methods disclosed herein. Forexample, the resultant polymer comprises repeating units selected from:

wherein R⁰ is selected from H, alkyl, NH₂, and R¹; wherein R¹ comprisesa crosslinking functionality; wherein repeating units A1, A2, B1, and B2account for at least about 50 wgt % of the polymer; and wherein theratio of (A1+A2):(B1+B2) is greater than 1.

In another aspect, the resultant polymer further comprises at least onerepeating unit formed from a monomer selected from:

or a combination thereof.

In one aspect, the method further comprises the step of crosslinking thepolymer with crosslinks, wherein the wherein the crosslinks comprises

wherein at least one of

is not 0.

In another aspect, the polymer is linear when the first compoundcomprises an ester moiety. In another aspect, the polymer issemi-branched when the first polymer comprises a glycidol moiety.Non-limiting examples of first compounds comprising an ester moiety are2-oxepane-1,5-dione and lactones, such as δ-valerolactone andα-allyl-δ-valerolactone. Non-limiting examples of first compoundscomprising a glycidol moiety are glycidol, allyl-glycidol ether,glycidyl ester allyl, and ethoxyethyl glycidyl ether. In one aspect, themethod comprises polymerizing the first compound comprising a glycidolmoiety and/or an ester moiety with a second compound comprising aglycidol moiety and/or a ester moiety, thereby making a copolymer. Inone aspect, the first compound comprises a glycidol moiety and thesecond compound comprises an ester moiety. In one aspect, the firstcompound comprises a glycidol moiety and the second compound comprises aglycidol moiety and an ester moiety.

In one aspect, the polymerization step is performed at a temperature offrom −30° C. to 50° C. In another aspect, the polymerization step isperformed at a temperature of from −30° C. to 20° C. In yet anotheraspect, the polymerization step is performed at a temperature of from−30° C. to 0° C. In yet another aspect, the polymerization step isperformed at a temperature of from −30° C. to −10° C.

Also disclosed herein is a method of crosslinking comprising: a)providing a first and second compound, wherein both the first and secondcompound comprises a crosslinking functionality; b) crosslinking thefirst and second compound with a crosslinks described herein.

F. Manufacture of a Medicament

In one aspect, the invention relates to a method for the manufacture ofa medicament for treatment of a disorder comprising combining adisclosed compound or nanoparticle with a therapeutically effectiveamount of a therapeutic agent, diagnostic agent, or prophylactic agent,or a mixture thereof and with a pharmaceutically acceptable carrier ordiluent.

G. Kits

Disclosed herein is a kit comprising a compound or nanoparticledisclosed herein and a therapeutic agent, diagnostic agent, orprophylactic agent, or a mixture thereof and one or more of: a)instructions of delivering the therapeutic agent, diagnostic agent, orprophylactic agent, or a mixture thereof; b) instructions for using thetherapeutic agent, diagnostic agent, or prophylactic agent, or a mixturethereof to treat a disorder.

H. Experimental

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

Efforts have been made to ensure accuracy with respect to numbers (e.g.,amounts, temperature, etc.), but some errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,temperature is in ° C. or is at ambient temperature, and pressure is ator near atmospheric.

As briefly discussed above, while hyperbranched systems formed throughthe polymerization of glycidol have shown applicability, the ability toform polymers with a controlled degree of branching was investigated. Inone aspect, controlled polymerization can allow the lower branchingsystems to achieve a better clearance but also allow the formation ofnanoparticles which is not possible with globular starticel materials.The semibraching retain some benefits of the hyperbranched systems forthe functionalization and hydrogels formation with and withoutstimuli-responsive reactions (FIG. 27-28). Without wishing to be boundby a particular theory, it is believed that the secondary reactionability will impart a wider range of versatility to the already robustpoly(glycidol) architecture. In a further aspect, the increase inpost-modification capability will increase the viability of thesynthesized polymer systems and allow for novel macromolecules. Asdepicted in FIG. 6, introduction of allyl functionalities, in oneaspect, can allow for the formation of a more robust polymer system withcrosslinking potential.

In a still further aspect, controlled degree of branching and linearsystems which can be synthesized more easily can used for targeteddelivery of drug molecules and biological cargo. In a yet furtheraspect, semi-branched structures with that are more favorable in vivo.

In various aspects, the ring opening polymerization of glycidol can beinfluenced kinetically. In the present example, the kinetic control onthe polymerization of poly(glycidol) was evaluated. To evaluate thekinetics of the polymer system, four temperatures were chosen in orderto undergo a thorough kinetic study on the ring opening polymerizationmechanism. The temperatures chosen are shown in Table 1, below. Thedegree of branching in the resultant polymers can be calculated usingequation 1 shown below, with the variables referring to the integrationvalues obtained from quantitative ¹³CNMR investigation, as further shownin FIG. 7. Unique peaks arise in the 13C-NMR based on the type of ringopening undergone by each monomer. The ¹³C-NMR of glycidol homopolymeris shown in FIG. 8.

$\begin{matrix}{{DB} = \frac{2D}{{2D} + L_{1,3} + L_{1,4}}} & \left( {{Eq}.\mspace{11mu} 1} \right)\end{matrix}$

For the purpose of direct correlation, the only variable that waschanged for each reaction was the temperature. NMR data and degree ofbranching for polyglycidol systems are reported in Table 1 below. Asshown in Table 1 and FIG. 9, kinetic control over the degree ofbranching in the polymer systems was accomplished by depressing thetemperature at which the reaction was conducted. Inspection of the NMRdata (FIG. 10) shows the suppression of the dendritic carbon peak whilethe linear peak remains strong. Thus, depressed reaction temperaturesreduce the formation of branches within the polymer backbone. In afurther aspect, these results allows for the determination of an optimalreaction temperature based on the degree of branching that is desiredfor the various applications proposed for the synthesized polymers.

TABLE 1 Glycidol Homopolymer Reaction Temperature (° C.) Region Shift(ppm) 40° C. 20° C. 0° C. −20° C. L_(1,3) 81.0-82.0 1.00 1.00 1.00 1.00D 79.5-80.5 0.79 0.62 0.60 0.48 2 L_(1,4) 73.5-74.5 3.69 3.65 3.98 4.802D, 2T 72.0-73.5 7.05 7.52 7.62 8.44 L_(1,3), L_(1,4) 70.5-72.0 3.143.01 3.17 2.93 T 64.0-65.0 1.74 2.13 2.17 3.53 L_(1,3) 62.0-63.5 3.152.97 2.76 2.87 Degree of Branching 0.24 0.21 0.20 0.15 RelativeAbundance of 10.5% 8.2% 8.0% 5.2% Dendritic Carbons Glycidol HomopolymerTemperature (° C.) Region Shift (ppm) 25° C. −5° C. −42° C. −78° C.L_(1,3) 81.0-82.0 1.00 1.00 1.00 1.00 D 79.5-80.5 0.78 0.41 0.35 0 2L_(1,4) 73.5-74.5 3.49 4.57 5.14 5.58 2D, 2T 72.0-73.5 7.55 8.99 7.548.42 L_(1,3), L_(1,4) 70.5-72.0 3.91 4.05 2.92 2.67 T 64.0-65.0 1.713.60 4.10 8.10 L_(1,3) 62.0-63.5 3.07 3.34 2.86 3.69 Degree of Branching0.2447 0.1272 0.1142 0

The capability to choose the degree of branching optimized for thepoly(glycidol) system affords the ability to modify the synthesizedpolymers based on the preferred application for each. This possibilityindicates that the present invention can be used in a wide range ofapplications with the reaction temperature being the determining factorfor the polymer architecture. Without wishing to be bound by aparticular theory, such control over this synthetic method allows formore effective and diverse potential. Poly(glycidol) branchingpossibilities are shown in FIGS. 11 and 12.

In various aspects, the glycidol monomer can be opened in two ways toyield different polymer units.[4, 22, 24, 36] As seen in FIG. 13, theserepeat units are known as linear-1,3 (L_(1,3)) and linear-1,4 (L_(1,4))and influence the branching that is seen in the polymer products. In astill further aspect, the undesired branching point can be alleviatedthrough two main methods: kinetically, as previously described, andthrough the use of glycidol derivatives.

In a further aspect, the use of the glycidol derivatives forces theepoxide ring to open exclusively into the L_(1,3) orientation. Whilethis is undesired in certain glycidol homopolymer embodiments, theabsence of the primary hydroxyl group does not allow branching of thepolymer to take place. In a still further aspect, the absence of theprimary hydroxyl group increases the linearity of the polymer productand, when coupled with depressed reaction temperatures, gives polymerswith very small degrees of branching. In a yet further aspect, the useof protected glycidol units can yield polymers that are completelylinear and can subsequently be deprotected to yield linear glycidolpolymers with the restored primary hydroxyl groups.[29]

The objective of the following example was to form a polymer with theincreased solubility of glycidol-based polymers but the biodegradabilityof polyesters. In a further aspect, a molecule was formulate thatincorporated the rapid reaction rate of glycidol with the physiologicaldegradability of polyesters. In a still further aspect, this formulationwould allow incorporation of the desired characteristics withoutsacrificing the low reaction conditions needed to impart a high degreeof linearity into the system.

In a first trial, glycidol was reacted directly with 4-pentenoylchloride. Despite the use of pyridine, the excess acid formed in thereaction was enough to cause an opening of the strained epoxide ring,yielding a mixture of products, none of which were desired, asrepresented by the reaction scheme below.

In a subsequent trial, an alternative method was used in which a diallylintermediate was employed following the reaction scheme below.

In order to achieve this molecule, 4-pentenoyl chloride was reacted with3-buten-1-ol in a 1:1 ratio to yield a diallyl species with an ester inthe center. This molecule was then oxidized using m-CPBA to afford aclear liquid product that was determined to have an epoxide on theoxygen side of the ester while maintaining the allyl functionality onthe carbonyl side.

As shown in FIG. 14, this new species was confirmed through 2-D NMRtechniques and appeared poised to overcome both the degradabilityproblems of homoglycidol systems as well as the homoglycidol system'slack of post-modification units.

Next, in order to force linearity into the system, a protected glycidolderivative was added to the list of possible monomers. Ethoxyethylglycidyl ether (EEGE) was chosen as a viable candidate as its protectedside arm is similar in bulk to that of the newly synthesized glycidylester allyl (GEA), following the reaction scheme below.

With the similar steric bulkiness, it was believed that both EEGE andGEA will polymerize at similar rates, allowing for a controlledcopolymerization of the two monomers. In a further aspect, the presenceof the EEGE can also allow for subsequent deprotection, which can yielda completely linear polymer with a plethora of hydroxyls, esters, andallyls.

Synthesis of Degradable and Non-Degradable Glycidol Based Copolymers

To remedy the physiological degradability issues as well as thepost-modification limitations of the glycidol homopolymers, a range ofcopolymers was produced. First, the degradability of the synthesizedpolymers was increased and subsequently an increased degree ofpost-modification units was introduced. These two problems were firstaddressed individually and then a more complete method was devised.

For increased degradability, first attempts were aimed at theincorporation of polyester sections into the backbone of the polymersthrough the incorporation of 8-valerolactone (VL) as a comonomer withthe glycidol monomer, according to the reaction scheme below.

However, the stringent reaction conditions that yield the lowestglycidol branching do not allow for a high incorporation of thelactones. The decision was made to give up some of the control over thebranching in order to increase the lactone incorporation. Unfortunately,the lowest temperature at which the polymerization could be run withoutthe lactone freezing was 10° C. Even at these elevated temperatures, thelarge difference in polymerization kinetics did not allow for a highdegree of incorporation.

Next, allyl glycidyl ether (AGE) was used to introduce allylfunctionalities into the backbone of the polymer, thus alleviating thepoor post-modification potential of poly(glycidol). This reaction, shownin the reaction scheme below, was successful, yielding polymers withallyl units dispersed throughout the structure.

However the lack of a readily degradable unit meant that the synthesizedpolymers could serve little purpose apart from illuminating thecross-linking ability of the new, semi-branched structures.

Next, the newly synthesized GEA monomer was incorporated into glycidol,according to the reaction scheme below.

Unfortunately, the successful synthesis of the novel GEA monomer specieswas followed by the monomer's lack-luster performance when copolymerizedwith glycidol. The drastic difference in polymerization kinetics,glycidol being very fast and GEA being rather slow, afforded a polymerproduct with truncated incorporation of the GEA monomer, appearing as afifth of what was intended. This realization led to the realization thata kinetic study of the GEA homopolymer is needed so that the optimalreaction conditions for the new monomer can be discovered. The NMR ofGLY/GEA polymer is shown in FIG. 15.

Synthesis of One-Pot Block Copolymer Structures

After determining that glycidol greatly outcompetes many lactonecomonomers, it was proposed that a glycidol homopolymer capped withester and allyl-containing units would be beneficial. In order toaccomplish this, glycidol polymers were formed according to thedetermined polymerization restrictions and small amounts ofα-allyl-δ-valerolactone (AVL) were added during the last hour of thepolymerization, as the reaction was allowed to return to roomtemperature. This subsequent addition of the degradable lactone monomerwas expected to add onto the end of the already formed poly(glycidol).The reaction scheme is shown below.

While ¹HNMR does show the inclusion of ally groups to the polymerproduct, since glycidol is such a kinetically favored monomer, it cannotbe determined if the product is actually a block copolymer or a randomcopolymer with a large glycidol “tail.”

Regardless of the actual morphology of the polymer product, theincorporation of the allyl groups should allow for subsequentconjugation to free thiols on the exterior of biological structures suchas proteins. It is believed that the attachment of these degradablehydrophilic polymers to proteins will increase the proteins' solubilityand provide a system that is more advantageous for protein delivery thanthe PEGylated protein structures that are currently in use.

Synthesis of Linear Polyesters

Next, formation of linear polyester systems was investigated.[7-10] Inone aspect, it was unknown whether tin triflate would yield polyesterpolymers similar to the ones obtained using the previously employed tinethyhlhexanoate. In another aspect, tin triflate is more reactive thantin ethylhexanoate due to the large electron withdrawing character ofits ligands. Therefore, in a further aspect, tin triflate is apreferential catalyst if it allows for the same control over polymersize and PDI as tin ethylhexanoate. First trials were performed using VLand AVL as copolymers according to the reaction scheme below.

The produced linear polymers exhibited correct size and distributionwith a faster reaction time and the ability to run the reaction at roomtemperature rather than elevated temperatures. Upon this positiveoutcome, further implementation of tin triflate was employed.

As depicted in FIG. 16, the addition of 2-oxepane-1,5-dione (OPD) to thebackbone of the linear polyester systems imparts a higher degree ofwater solubility to the system.[7, 9, 10] Since this increasedhydrophilicity is beneficial for the eventual use of the linearpolyesters as the building blocks for nanoparticle drug deliverysystems, a range of OPD containing VL/AVL polymers were evaluated tostudy its influence on the system.

The resulting polymer products contained OPD percentages ranging from5%-40%. Furthermore, the purification of the polymer had to undergo achange. Rather than precipitating in methanol, as done with VL/AVLpolymers, the new OPD containing polymers must be dialyzed against DCMas they do not precipitate in methanol. As expected, with the increasein OPD, there was an increase in the degree of water solubility. Thesenew OPD polymers will be used for the formation of nanoparticles withincreased hydrophilicity that will be employed as drug deliveryvehicles. The exemplary reaction scheme below shows the synthesis ofVL/AVL/OPD linear polymer according to the above method.

Synthesis of Novel Crosslinker Molecules for the Formation ofNanoparticles

As described herein, the present invention, in one aspect, also involvesnovel cross-linking molecules. In a further aspect, the cross-linkingmolecules have the ability to be protonated. In another aspect, thepresent invention also relates to the delivery of biological structureswith the nanoparticles using the cross-linking molecules. In a furtheraspect, the protonation capacity is important since biologicalstructures, such as siRNA will be held more tightly by the positivecharges than they would be if the cross-linking of the polymers was theonly method being employed to contain the biological structures in thenanoparticles. In a still further aspect, the efficacy of this approachhas recently been illuminated in dendritic polyglycerol species.[37]

In a first example, a protected dithiol species was employed. Thedisulfide was attached to a carboxylic acid and subsequently reactedwith 0.5 equivalents of a diamine species, affording a molecule withsecondary amine species and readily accessible thiol groups. The thiolgroups were used for “click” reactions[8] in order to form nanoparticles(FIG. 17), while the secondary amines were used to increase thecomplexation of siRNA into the system (FIG. 18). [37, 40] The exemplaryreaction scheme below shows the formation of a nanoparticle inaccordance with the above method.

The final step in the formation of the nanoparticle drug delivery systemis the collapsing of the polymers into nanoparticles. In one aspect,this reaction was conducted by two separate methods. In a furtheraspect, the methods include thiolene-click reactions[8](FIG. 19) andamine-epoxide reactions[7, 10](FIG. 20). In still further aspect, thetwo methods can also be employed in the formation of polyesternanoparticles as well as the synthesis of novel polyglycerol structures.The exemplary reaction scheme in FIG. 21 shows thiolene-click GLY/AGEnanoparticle formation.

Next, to evaluate the viability of the nanoparticle systems, drugloading and release studies were performed. As depicted in FIG. 22, anumber of small molecule drugs including Paclitaxel, Bromonidine, andTemozolomide, were chosen to be loaded into the polyester nanoparticles.The percentage of drug incorporation was determined using a nano-dropmethod based on UV/VIS absorption. The drug release profiles of thesesystems was studied by dissolving the loaded nanoparticles in aphysiological pH buffer and allowing the solution to stir at 37° C. Thebuffer was changed every 48 hours and the excreted drug was extractedusing DCM and quantified using nanoDrop. Similar techniques will beemployed in order to study the drug loading and release capabilities ofthe newly synthesized poly(glycidol) based systems.

Dual Component Delivery System

In various aspects, the present invention also relates to a twocomponent delivery system. In a further aspect, the dual component drugdelivery system can deliver 2 classes of therapeutics. For example, inone aspect, a dual component drug delivery system can help achieve boneunion following fracture in patients with neurofibromatosis (NF1). Thesepatients cannot heal their bone and require amputation. In a furtheraspect, mouse models can recapitulate this skeletal complication. Thus,in a still further aspect, in this example the objective was to combinesmall molecules, such as MEK inhibitors, and BMP2 growth factors topromote bone union (FIG. 27).

In another aspect, the present invention provides a reconfigurable andresponsive network system (FIG. 28). In a further aspect, the networksystems comprise functionalized polyglycidol-based crosslinkingmaterials for hydrogels with functionalized polyesters orpolycarbonates. In a still further aspect, the network systems cancomprise functionalized polyglycidols crosslinked with functionalizeddegradable materials such as linear polyesters and polycarbonates. Inone aspect, the networks can be reconfigured and are not thermosets, butrather act as vitrimers.

These networks are are not “set” in the presence of the Zn(Ac)₂, and thefree —OH groups of the polyclidol can react with available esters,making the polymers therefore stimuli responsive. In an even furtheraspect, the networks systems are reconfigurable and are not set.Exemplary reactions for forming functionalized polyglycidols in anetwork system are shown in FIG. 29.

I. Experimental Examples

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Starting materials and therequisite intermediates are in some cases commercially available, or canbe prepared according to literature procedures or as illustrated herein.

The following exemplary compounds of the invention were synthesized. TheExamples are provided herein to illustrate the invention, and should notbe construed as limiting the invention in any way. The Examples aretypically depicted in free base form, according to the IUPAC namingconvention. However, some of the Examples were obtained or isolated insalt form.

As indicated, some of the Examples were obtained as racemic mixtures ofone or more enantiomers or diastereomers. The compounds may be separatedby one skilled in the art to isolate individual enantiomers. Separationcan be carried out by the coupling of a racemic mixture of compounds toan enantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. A racemicor diastereomeric mixture of the compounds can also be separateddirectly by chromatographic methods using chiral stationary phases.

1. General Methods

All reagent chemicals were purchased from Sigma-Aldrich, StremChemicals, or Acros and used as received unless otherwise noted. Them-CPBA (77%) was purified as previously reported in the literature whileδ-valerolactone and glycidol was further purified through vacuumdistillation. SnakeSkin® Pleated Dialysis Tubing, regenerated cellulose,was purchased from Pierce Biotechnology. Spectra/Por® Dialysis membranewas purchased from Spectrum Laboratories Inc. α-allyl-δ-valerolactone,α-propargyl-δ-valerolactone, and 2-oxepane-1,5-dione were synthesized aspreviously reported in the literature.

¹H and ¹³C NMR were obtained from a Bruker AV-I 400 MHz, a Bruker DRX500 MHz, or a Bruker AV-II 600 MHz spectrometer. The reported chemicalshifts are in ppm and are in reference to the corresponding residualnuclei in deuterated solvents.

Gel-permeation chromatography (GPC) was carried out with a Waterschromatograph system equipped with a Waters 2414 refractive indexdetector, a Waters 2481 dual 2 absorbance detector, a Waters 1525 binaryHPLC pump, and four 5 mm Waters columns (300 mm×7.7 mm), connected inseries with increasing pore size (100, 1000, 100,000 and 1,000,000 Årespectively). All runs were performed with N—N-dimethylformamide (DMF)as the eluent at a flow rate of 1 mL/min.

Samples for transmission electron microscopy (TEM) imaging were preparedby dissolving 0.5 mg nanoparticles in 1 mL isopropanol, 0.3 mLacetonitrile and 0.2 mL toluene. The samples were sonicated for 5 minand were stained with 3 drops of 3% phosphotungstic acid. The carbongrids were prepared by slowly dipping an Ultrathin Carbon Type-A 400Mesh Copper Grid (Ted Pella, Inc., Redding, Calif.) into the particlesolutions three times and drying the grid at ambient temperature. APhilips CM20T transmission electron microscope operating at 200 kV inbright-field mode was used to obtain TEM micrographs of the polymericnanoparticles. FIG. 23 shows the DLS (Nanosight instrument), depictingthe minimal size dispersity of nanoparticle structures (I 15 nm).

2. Preparation of Glycidol Polymers

A. General Procedure

A 25 mL and a 10 mL round bottom flask were flame-dried under N₂(g),along with a 50 mL 3-neck round bottom flask equipped with a stir bar.In the 25 mL round bottom flask, an 1.7M Iso-Amyl alcohol (IAOH) stocksolution was formed using dry THF, while the 10 mL round bottom flaskwas used to create a 3.7×10⁻²M tin triflate stock solution, also usingdry THF. The stock solutions were then allowed to sit for 30 minutesbefore adding Sn(OTf)₂ (0.00035 eq) and IOAH (0.066 eq) to the reactionflask. The reaction flask was then brought to the proper reactiontemperature before adding the monomers (1.0 and allowing thepolymerization to run to completion. Figures are shown using an ethanolinitiator (EtOH) instead of the IAOH. The use is optional but the IAOHis preferred because the polymer products can be more accuratelycharacterized. The protons from IAOH do not overlap with polymer peaksand the polymer molecular weight can be determined via ¹H-NMR.

Preparation of GLY Homopolymer

Sn(OTf)₂ (0.26 mL; 9.45×10⁻⁶ mol; 0.00035 eq) and IAOH (0.20 mL;3.33×10⁻⁴ mol; 0.066 eq) were added to the reaction flask, which wasthen lowered into an acetone/dry ice bath at −42° C. The flask wasallowed to cool completely before adding the glycidol (2.00 g; 27.00mmol; 1.0 eq) monomer. The reaction was then allowed to run for 8 hwhile maintaining the depressed temperature. After 8 h the resultingviscous polymer product was precipitated into vigorously stirringhexanes affording a clear viscous product. The hexanes were decantedfrom the product, which was then transferred to a 6-dram vial, usingmethanol. Yield: 1.896 g (94.82%). ¹H-NMR (600 MHz, CDCl₃) δ: 3.31-3.94(6H). ¹³C-NMR (150 MHz, CDCl₃) δ: 81.37, 79.81, 75.12, 73.88,72.01-72.94, 70.42-71.17, 64.41, 62.53, 62.06.

(1) Preparation of GLY/AGE Polymer (80/20)

Sn(OTf)₂ (0.23 mL; 8.52×10⁻⁶ mol; 0.00035 eq) and EtOH (0.196 mL;3.33×10⁻⁴ mol; 0.066 eq) were added to the reaction flask, which wasthen lowered into an acetonitrile/dry ice bath at −42° C. The flask wasallowed to cool completely before adding the glycidol (1.44 g; 19.47mmol; 4.0 eq) and glycidyl ether (0.56 g; 4.87 mmol; 1.0 eq). Thereaction was then allowed to run for 8 h while maintaining the depressedtemperature. After 8 h the resulting viscous polymer product wasprecipitated into vigorously stirring hexanes affording a clear viscousproduct. The hexanes were decanted from the product, which was thentransferred to a 6-dram vial, using methanol. Yield: 2.05 g (68.27%).¹H-NMR (600 MHz, CDCl₃) δ: 5.92 (1H), 5.21 (2H), 4.04 (2H), 3.38-3.94(27.30H). ¹³C-NMR (150 MHz, CDCl₃) δ: 136.31, 117.42, 81.56, 80.01,74.09, 73.43, 72.51, 70.87, 64.60, 62.69.

(2) Preparation of GEA Homopolymer

Sn(OTf)₂ (0.056 mL; 2.06×10⁻⁶ mol; 0.00035 eq) and IAOH (0.098 mL;1.67×10⁻⁴ mol; 0.066 eq) were added to the reaction flask, which wasthen lowered into an acetonitrile/dry ice bath at −42° C. The flask wasallowed to cool completely before adding the previously synthesizedglycidyl ester allyl (1.0 g; 5.88 mmol; 1.0 eq). The reaction was thenallowed to run for 8 h while maintaining the depressed temperature.After 8 h the resulting viscous polymer product was precipitated intovigorously stirring hexanes affording a clear viscous product. Thehexanes were decanted from the product, which was then transferred to a6-dram vial, using methanol. Yield: 230.8 mg (23.08%). ¹H-NMR (600 MHz,CDCl₃) δ: 5.83 (1H), 5.00 (2H) 4.61 (5H), 3.39-3.82 (19.06H), 2.24-2.66(23.33H) 2.12 (6.17H) 1.56-1.92 (4.87H). ¹³C-NMR (150 MHz, CDCl₃) δ:180.40, 174.87, 138.14, 136.53, 135.64, 117.62, 115.98, 81.31, 79.58,70.84, 67.32, 66.52, 64.62, 60.05, 37.16, 34.39, 31.13, 29.55, 24.51.

(3) Preparation of GLY/GEA Polymer (80/20)

Sn(OTf)₂ (0.10 g; 3.75×10⁻⁶ mol; 0.00035 eq) and EtOH (0.10 mL;1.67×10⁻⁴ mol; 0.066 eq) were added to the reaction flask, which wasthen lowered into an acetonitrile/dry ice bath at −42° C. The flask wasallowed to cool completely before adding the glycidol (0.64 g; 8.57mmol; 4.0 eq) and the previously synthesized glycidyl ester allyl (0.36g; 2.14 mmol; 1.0 eq). The reaction was then allowed to run for 8 hwhile maintaining the depressed temperature. After 8 h the resultingviscous polymer product was precipitated into vigorously stirringhexanes affording a clear viscous product. The hexanes were decantedfrom the product, which was then transferred to a 6-dram vial, usingmethanol. Yield: 633.7 mg (63.37%). ¹H-NMR (600 MHz, CDCl₃) δ: 5.93(1H), 5.27 (2.37H), 4.06-4.28 (2.91H) 3.26-3.98 (303.6H), 2.24-2.63(8.25H), 1.84 (2.57H), 1.65 (18.67H). ¹³C-NMR (150 MHz, CDCl₃) δ:138.53, 72.90, 71.32, 63.42, 61.52, 26.55.

(4) Preparation of GLY/MLGEA Polymer (80/20)

Sn(OTf)₂ (0.10 g; 3.75×10⁻⁶ mol; 0.00035 eq) and EtOH (0.10 mL;1.67×10−4 mol; 0.066 eq) were added to the reaction flask, which wasthen lowered into an acetonitrile/dry ice bath at −42° C. The flask wasallowed to cool completely before adding the glycidol (0.64 g; 8.84mmol; 4.0 eq) and the previously synthesized mixed-length glycidyl esterallyl (0.35 g; 2.21 mmol; 1.0 eq). The reaction was then allowed to runfor 8 h while maintaining the depressed temperature. After 8 h theresulting viscous polymer product was precipitated into vigorouslystirring hexanes affording a clear viscous product. The hexanes weredecanted from the product, which was then transferred to a 6-dram vial,using methanol. ¹H-NMR (600 MHz, CDCl₃) δ:5.83 (1H), 5.07 (2.37H),3.97-4.21 (1.74H) 3.29-3.95 (97.12H), 2.26-2.61 (4.95H), 1.82 (1.61H),1.65 (7.54H).

(5) Preparation of EEGE Homopolymer

Sn(OTf)₂ (0.032 mL; 1.20×10⁻⁶ mmol; 0.00035 eq) and EtOH (0.049 mL;8.33×10⁵ mmol; 0.066 eq) were added to the reaction flask. Thesynthesized ethoxyethyl glycidyl ether (0.5 g; 3.42 mmol; 1.0 eq) wasthen added. The reaction was then allowed to run for 24 h at roomtemperature. After 24 h the resulting viscous polymer product wasprecipitated into vigorously stirring hexanes affording a whitishviscous product. Yield: 196.5 mg (39.3%). The hexanes were decanted fromthe product, which was then transferred to a 6-dram vial, usingmethanol. ¹H-NMR (500 MHz, CDCl₃) δ: 4.16 (1H), 3.87 (1.21H), 3.39-3.81(19.28H), 1.64 (5.54H), 1.23 (8.08H), 0.86 (2.92H).

(6) Preparation of EEGE/GEA Polymer (80/20)

Sn(OTf)₂ (0.0313 mL; 1.16×10⁻⁶ mmol; 0.00035 eq) and EtOH (0.049 mL;8.33×10−5 mmol; 0.066 eq) were added to the reaction flask. The stocksolutions were allowed to stir for 10 minutes before adding theδ-valerolactone (1.48 g; 14.80 mmol; 4.0 eq) and α-allyl-δ-valerolactone(0.52 g; 3.70 mmol; 1.0 eq). The reaction was then allowed to run for 24h at room temperature. After 24 h the resulting viscous polymer productwas precipitated into cold diethyl ether to afford the off-whiteparticulate polymer product. The diethyl ether was decanted from theproduct, which was then transferred to a 6-dram vial, using ethylacetate. Yield: 374.9 mg (74.98%). ¹H-NMR (500 MHz, CDCl₃) δ: 4.28 (1H),3.43-3.78 (6.43H), 3.17 (1.32H), 2.35 (3.36H), 2.02 (2.84H), 1.65(10.42H), 1.29 (69.79H), 0.92 (37.31H).

(7) Preparation of EEGE/MLGEA Polymer (80/20)

Sn(OTf)₂ (0.0313 mL; 1.16×10⁻⁶ mmol; 0.00035 eq) and EtOH (0.049 mL;8.33×10−5 mmol; 0.066 eq) were added to the reaction flask. The stocksolutions were allowed to stir for 30 minutes before adding the EEGE(1.36 g; 14.54 mmol; 4.0 eq) and MLGEA (0.47 g; 3.36 mmol; 1.0 eq). Thereaction was then allowed to run for 24 h at 70° C. After 24 h theresulting viscous polymer product was precipitated into methanol toafford the off-white particulate polymer product. The methanol wasdecanted from the product, which was then transferred to a 6-dram vial,using ethyl acetate.

(8) Preparation of GLY/VL Polymer (80/20)

Sn(OTf)₂ (024 mL; 8.82×10⁻⁶ mmol; 0.00035 eq) and EtOH (0.20 mL;3.33×10⁻⁴ mmol; 0.066 eq) were added to the reaction flask, which wasthen lowered into a salt water/ice bath at −20° C. The flask was allowedto cool completely before adding the glycidol (1.49 g; 20.16 mmol; 4.0eq) and δ-valerolactone (0.50 g; 5.04 mmol; 1.0 eq). The reaction wasthen allowed to run for 8 h while maintaining the depressed temperature.After 8 h the resulting viscous polymer product was precipitated intovigorously stirring hexanes affording a whitish viscous product. Thehexanes were decanted from the product, which was then transferred to a6-dram vial, using methanol. Yield: 1.54 g (77%). ¹H-NMR (600 MHz,CDCl₃) δ:4.10 (1H), 3.89 (1.17H), 3.41-3.82 (18.48H), 3.33 (7.66H), 2.37(1.36H, 1.51-1.76 (4.29H). ¹³C-NMR (150 MHz, CDCl₃) δ: 138.52, 72.96,71.38, 69.70, 64.07, 33.50, 28.15, 21.59.

(9) Preparation of GLY/VL/AVL Polymer (60/20/20)

Sn(OTf)₂ (0.20 mL; 7.56×10⁻⁶ mmol; 0.00035 eq) and EtOH (0.20 mL;3.33×10⁻⁴ mmol; 0.066 eq) were added to the reaction flask, which wasthen lowered into a salt water/ice bath at −20° C. The flask was allowedto cool completely before adding the glycidol (0.96 g; 12.96 mmol; 3.0eq), δ-valerolactone (0.61 g; 4.32 mmol; 1.0 eq), andα-allyl-δ-valerolactone (0.43 g; 4.32 mmol; 1.0 eq). The reaction wasthen allowed to run for 8 h while maintaining the depressed temperature.After 8 h the resulting viscous polymer product was precipitated intovigorously stirring hexanes affording a whitish viscous product. Thehexanes were decanted from the product, which was then transferred to a6-dram vial, using methanol. Yield: 528.4 mg (35.23%). ¹H-NMR (600 MHz,CDCl₃) δ: 5.77 (1H), 5.05 (2H), 4.13 (7.46H), 3.29-4.03 (171.73H), 2.38(14.37H), 1.66 (34.73H), 1.22 (7.25H). 13C-NMR (150 MHz, CDCl₃) δ:175.82, 136.74, 117.21, 83.16, 81.40, 79.83, 73.85, 72.25, 64.44, 62.45,37.65, 34.53, 32.94, 31.29, 30.04, 29.24, 27.44, 22.46, 15.49, 14.63.

(10) Preparation of GLY/VL/PO/AGE Polymer (50/20/20/10)

Sn(OTf)₂ (5.83 mg; 1.28×10⁻⁵ mol; 0.00035 eq) and EtOH (0.012 mL;2.07×10⁻⁴ mol; 0.066 eq) were added to the reaction flask, which wasthen lowered into a salt water/ice bath at −20° C. The flask was allowedto cool completely before adding the glycidol (0.47 g; 6.38 mmol; 5.0eq), δ-valerolactone (0.26 g; 2.56 mmol; 2.0 eq), propylene oxide (0.15g; 2.56 mmol; 2.0 eq), and allyl glycidyl ether (0.15 g; 1.28 mmol; 1.0eq). The reaction was then allowed to run for 8 h while maintaining thedepressed temperature. After 8 h the resulting viscous polymer productwas precipitated into vigorously stirring hexanes affording a whitishviscous product. The hexanes were decanted from the product, which wasthen transferred to a 6-dram vial, using methanol. Yield: 218.2 mg(21.82%). ¹H-NMR (600 MHz, CDCl₃) δ: 5.92 (1H), 5.22 (2.05H), 4.03(2.36H), 3.29-3.96 (54.76H), 2.16 (1.09H), 1.68 (1.81H), 1.30 (3.74H),1.15 (10.64H). ¹³C-NMR (150 MHz, CDCl₃) δ: 207.26, 176.02, 136.26,117.50, 7.70, 74.01, 73.39, 72.28, 70.73, 62.51, 52.22, 34.59, 33.02,22.53.

(11) Oxidation of GLY/AGE Polymer (80/20)

To a round bottom flask equipped with a stir bar, was added the GLY/AGEpolymer (1.0 eq), m-CPBA (0.1 eq), and methanol (5.4×10⁻² g/mL). Theround bottom flask was then capped with a septum and allowed to stir for72 h at room temperature. The resulting product solution was thenconcentrated and precipitated into vigorously stirring hexanes. Thehexane was decanted from the product, which was then transferred to a6-dram vial using methanol. Yield: 128.2 mg (24.97%). ¹H-NMR (600 MHz,CDCl₃) δ: 5.93 (1H), 5.26 (2.01H), 4.03 (1.96H), 3.89 (4.00H), 3.38-3.81(53.76H), 3.31 (1.07H), 1.65 (5.33H). ¹³C-NMR (150 MHz, CDCl₃) δ:136.26, 117.40, 81.47, 79.92, 79.27, 74.02, 72.41, 70.72, 64.54, 62.63,27.73.

3. Preparation of Monomers

(1) Purification of M-CPBA

m-CPBA (70 g; 77%) was dissolved in diethyl ether (500 mL) andtransferred to a separatory funnel. The ether layer was then washed 3×with 300 mL aliquots of buffer solution (410 mL 0.1M NaOH, 250 mL 0.2MKH₂PO₄, made up to 1 L; pH≈7.5). The ether layer was dried over MgSO₄and then evaporated on the rotovap to yield the pure white m-CPBAproduct.[41]¹H-NMR (400 MHz, CDCl₃) δ: 8.14-8.08 (2H, m, CH, CH), 7.82(1H, d, CH), 7.59 (1H, m, CH).

(2) Preparation of a-allyl-Δ-valerolactone

This reaction was performed as previously described in literature withthe added use of vacuum distilled δ-valerolactone rather than using thepurchased purity.[7, 9, 10] Yield: 2.56 g (46.12%) ¹H-NMR (400 MHz,CDCl₃) δ: 5.80 (1H, m, CH) 5.04 (2H, m, CH₂), 4.27 (2H, m, CH₂), 2.42(2H, m, CH₂, CH), 2.18 (1H, m, CH₂), 2.00-1.72 (4H, m, CH₂). ¹³C-NMR(100 MHz, CDCl₃) δ: 173.98, 135.03, 117.54, 68.84, 39.13, 35.42, 22.13,21.05.

(3) Preparation of a-propargyl-Δ-valerolactone

This reaction was performed as previously described in literature withthe added use of vacuum distilled δ-valerolactone rather than using thepurchased purity.[7, 9, 10] Yield: 2.08 g (53.64%). ¹H-NMR (400 MHz,CDCl₃) δ: 4.34 (2H, m, CH₂), 2.71 (1H, m, CH), 2.51 (1H, m, CH₂), 2.37(1H, m, CH), 2.24 (1H, m, CH₂), 2.00-1.73 (4H, m, CH₂). 13C-NMR (125MHz, CDCl₃) δ: 171.96, 81.75, 70.14, 68.98, 39.02, 24.21, 21.87, 20.43.

(4) Preparation of 2-oxepane-1,5-dione

This reaction was performed as previously described in literature withthe added use of purified m-CPBA rather than using the purchasedpurity.[7, 9, 10] Yield: 1.89 g (54.31%). ¹H-NMR (400 MHz, CDCl₃) δ:4.36 (2H, t, CH₂), 2.76 (2H, m, CH₂), 2.65 (2H, m, CH₂), 2.59 (2H, m,CH₂). ¹³C-NMR (125 MHz, CDCl₃) δ: 205.14, 173.57, 63.74, 44.86, 38.94,28.31.

(5) Preparation of Diallyl Ester

To a round bottom flask equipped with a stir bar, was added 3-buten-1-ol(3.27 g; 45.29 mmol; 1.0 eq) and DCM (25 mL; excess). A diluted solutionof 4-pentenoyl chloride (5.37 g; 45.29 mmol; 1.0 eq) and DCM (25 mL;excess) was created in an addition funnel. The 4-pentenoyl chloridesolution was then added drop wise to the stirring reaction mixture over30 minutes and the reaction was allowed to run for 3 h until TLCindicated the reaction was complete. The excess solvent was then removedon the rotovap to afford the crude product. The resulting crude liquidproduct was on the Biotage column system using a gradient of 8%-70%ethyl acetate in hexanes to yield the pure clear liquid product. Yield:10.33 g (73.95%). ¹H-NMR (500 MHz, CDCl₃/TMS) δ 5.78 (2H, m, CH), 5.07(4H, m, CH₂), 4.12 (2H, t, CH₂O), 2.38 (6H, m, 3CH₂). ¹³C-NMR (125 MHz,CDCl₃) δ 173.22, 136.89, 134.22, 117.38, 115.65, 63.61, 33.73, 33.28,29.07.

(6) Preparation of Glycidyl Ester Allyl

To a round bottom flask equipped with a stir bar, was added thepreviously synthesized diallyl ester (2.90 g; 18.79 mmol; 1.0 eq),m-CPBA (3.24 g; 18.79 mmol; 1.0 eq), and DCM (53.66 mL; 5.4×10⁻² g/mL).The oxidation reaction was then allowed to run for 48 h. The crudeproduct was then vacuum filtered to remove the white precipitate beforeextracting the filtrate with saturated sodium bicarbonate to remove anyunreacted m-CPBA. The excess DCM was then removed on the rotovap toafford the clear crude liquid product. The resulting crude liquidproduct was purified on the Biotage column system using a gradient of8%-70% ethyl acetate in hexanes to yield the pure clear liquid product.Yield: 6.83 g (60.47%). ¹H-NMR (500 MHz, CDCl₃) δ 5.82 (1H, m, CH), 5.09(2H, m, CH₂), 4.41 (1H, dd, CH₂), 3.93 (1H, q, CH₂), 3.21 (1H, sext,CH), 2.85 (1H, t, CH₂), 2.65 (1H, q, CH₂), 2.47 (2H, m, CH₂), 2.40 (2H,m, CH₂). ¹³C-NMR (125 MHz, CDCl₃) δ 174.27, 138, 116.06, 66.23, 50.42,45.13, 34.27, 29.96.

(7) Preparation of Mixed Length Diallyl Ester

To a round bottom flask equipped with a stir bar, was added allylalcohol (3.27 g; 45.29 mmol; 1.0 eq) and DCM (25 mL; excess). A dilutedsolution of 4-pentenoyl chloride (5.37 g; 45.29 mmol; 1.0 eq) and DCM(25 mL; excess) was created in an addition funnel. The 4-pentenoylchloride solution was then added drop wise to the stirring reactionmixture over 30 minutes and the reaction was allowed to run for 3 huntil TLC indicated the reaction was complete. The excess solvent wasthen removed on the rotovap to afford the crude product. The resultingcrude liquid product was purified on the Biotage column system using agradient of 8%-70% ethyl acetate in hexanes to yield the pure clearliquid product. ¹H-NMR (500 MHz, CDCl₃/TMS) δ 5.78 (2H, m, CH), 5.09(4.11H, m, CH₂), 4.12 (2H, t, CH₂O), 2.39 (6.4H, m, 3CH₂).

(8) Preparation of Mixed Length Glycidyl Ester Allyl

To a round bottom flask equipped with a stir bar, was added thepreviously synthesized mixed length diallyl ester (2.90 g; 18.79 mmol;1.0 eq), m-CPBA (3.24 g; 18.789 mmol; 1.0 eq), and DCM (53.657 mL;5.4×10⁻² g/mL). The oxidation reaction was then allowed to run for 48 h.The crude product was then vacuum filtered to remove the whiteprecipitate before extracting the filtrate with saturated sodiumbicarbonate to remove any unreacted m-CPBA. The excess DCM was thenremoved on the rotovap to afford the clear crude liquid product. Theresulting crude liquid product was purified on the Biotage column systemusing a gradient of 8%-70% ethyl acetate in hexanes to yield the pureclear liquid product. ¹H-NMR (500 MHz, CDCl₃) δ 5.88 (2H, m, CH), 5.22(4.54H, m, CH₂), 2.95 (2.19H, m), 2.72 (2.58H, t), 1.94 (3.06H, m),1.75, 2.87H).

(9) Preparation of Ethoxyethyl Glycidol Ether

To a round bottom flask equipped with a stir bar was added glycidol(7.41 g; 100 mmol; 1.0 eq) and ethyl vinyl ether (27.88 g; 386.67 mmol;3.87 eq). The reaction flask was then lowered into a salt water/ice bathat 0° C. and began stirring. P-toluene sulfonic acid (185.2 mg; 0.97mmol; 0.0097 eq) was then added slowly portionwise in order to maintainthe low reaction temperature. The mixture was then allowed to stir atthe depressed temperature for 7 h. The reaction was then quenched withsaturated NaHCO₃ (excess). The organic layer was then separated, driedand evaporated on the rotovap to yield to monomer product. Yield: 182.6mg (32.47%). ¹H-NMR (400 MHz, CDCl₃) δ: 4.73 (1.95H), 4.09 (1H), 3.78(1H), 3.66 (3.15H), 3.51 (2.95H), 2.77 (2.01H), 2.61 (1.98H), 1.29(6.18H), 1.17 (7.97H). ¹³C-NMR (100 MHz, CDCl₃) δ: 171.21, 99.76, 65.86,65.19, 60.98, 50.89, 44.64, 21.12, 19.72, 15.35, 14.29.

4. Preparation of Polyesters

A. General Procedure for VL Based Polymers

A 25 mL and a 10 mL round bottom flask were flame-dried under N₂(g),along with a 50 mL 3-neck round bottom flask equipped with a stir bar.In the 25 mL round bottom flask, an 1.7M EtOH stock solution was formedusing dry THF, while the 10 mL round bottom flask was used to create a3.7×10⁻²M tin triflate stock solution, also using dry THF. The stocksolutions were then allowed to sit for 30 minutes before adding Sn(OTf)₂(0.00035 eq) and EtOH (0.066 eq) to the reaction flask. The reactionflask was then brought to the proper reaction temperature before addingthe monomers and allowing the polymerization to run to completion.

(1) Preparation of VL Homopolymer

Sn(OTf)₂ (0.19 mL; 6.99×10⁻⁶ mmol; 0.00035 eq) and EtOH (0.29 mL; 5×10⁻⁴mmol; 0.066 eq) were added to the reaction flask. The stock solutionswere allowed to stir for 10 minutes before adding the δ-valerolactone(2.70 g; 19.98 mmol; 1.0 eq) monomer. The reaction was then allowed torun for 24 h at room temperature. After 24 h the resulting viscouspolymer product was precipitated into cold diethyl ether to afford theoff-white particulate polymer product. The diethyl ether was decantedfrom the product, which was then transferred to a 6-dram vial, usingethyl acetate. Yield: 1.83 g (91.5%). ¹H-NMR (400 MHz, CDCl₃) δ: 4.07(82.79H), 3.63 (6.44H), 3.46 (101.51H), 2.33 (93.10H), 2.21 (33.20H),1.67 (168.64H), 1.25 (3H). ¹³C-NMR (100 MHz, CDCl₃) δ:173.62, 63.89,62.18, 50.60, 33.62, 32.06, 27.98, 21.34.

(2) Preparation of VL/AVL Linear Polymer (80/20)

Sn(OTf)₂ (0.19 mL; 6.99×10⁶ mmol; 0.00035 eq) and EtOH (0.29 mL; 5×10⁻⁴mmol; 0.066 eq) were added to the reaction flask. The stock solutionswere allowed to stir for 10 minutes before adding the δ-valerolactone(1.48 g; 14.80 mmol; 4.0 eq) and α-allyl-δ-valerolactone (0.52 g; 3.70mmol; 1.0 eq). The reaction was then allowed to run for 24 h at roomtemperature. After 24 h the resulting viscous polymer product wasprecipitated into cold diethyl ether to afford the off-white particulatepolymer product. The diethyl ether was decanted from the product, whichwas then transferred to a 6-dram vial, using ethyl acetate. Yield:1.3815 g (69.08%). ¹H-NMR (400 MHz, CDCl₃) δ: 5.72 (1H), 5.03 (2H), 4.08(11.52H), 2.35 (11.77H), 1.67 (24.01H), 1.27 (1.85H). ¹³C-NMR (100 MHz,CDCl₃) δ: 175.30, 173.42, 135.36, 117.11, 64.07, 62.37, 60.50, 44.98,36.59, 33.93, 32.23, 28.23, 26.57, 21.57, 21.28, 14.39.

(3) Preparation of VL/OPD/AVL Linear Polymer (60/20/20)

Sn(OTf)₂ (0.30 mL; 8.83×10⁻⁶ mmol; 0.00035 eq) and EtOH (0.29 mL;3.33×10⁻⁴ mmol; 0.066 eq) were added to the reaction flask. The stocksolutions were allowed to stir for 10 minutes before adding theδ-valerolactone (1.92 g; 19.20 mmol; 3.0 eq), 2-oxepane-1,5-dione (0.82g; 6.40 mmol; 1.0 eq), and the previously synthesizedα-allyl-δ-valerolactone (0.90 g; 6.40 mmol; 1.0 eq). The reaction wasthen allowed to run for 24 h at room temperature. After 24 h theresulting viscous polymer product was precipitated into cold diethylether to afford the off-white particulate polymer product. The diethylether was decanted from the product, which was then transferred to a6-dram vial, using ethyl acetate. Yield: 2.912 g (97.07%). ¹H-NMR (400MHz, CDCl₃) δ: 5.71 (1H, m, CH), 5.03 (2H, m, CH₂), 4.34 (2H), 4.08(10.79H), 3.67 (1.04H), 2.52-2.86 (6.68H), 2.15-2.51 (13.22H), 1.67(22.63H). ¹³C-NMR (100 MHz, CDCl₃) δ: 135.33, 117.73, 69.64, 68.76,64.11, 39.57, 35.71, 33.89, 30.05, 28.26, 24.36, 22.53, 21.61, 19.33.

(4) Preparation of VL/PVL/OPD Linear Polymer (70/20/10)

Sn(OTf)₂ (0.26 mL; 9.50×10⁻⁶ mmol; 0.00035 eq) and EtOH (0.29 mL; 5×10⁻⁴mmol; 0.066 eq) were added to the reaction flask. The stock solutionswere allowed to stir for 10 minutes before adding the δ-valerolactone(1.90 g; 19.00; 7.0 eq), the previously synthesizedα-propargyl-δ-valerolactone (0.75 g; 5.43 mmol; 2.0 eq), and thepreviously synthesized α-propargyl-δ-valerolactone 2-oxepane-1,5-dione(0.35 g; 2.71 mmol; 1.0 eq). The reaction was then allowed to run for 24h at room temperature. After 24 h the resulting viscous polymer productwas precipitated into cold diethyl ether to afford the off-whiteparticulate polymer product. The diethyl ether was decanted from theproduct, which was then transferred to a 6-dram vial, using ethylacetate. Yield: 1.58 g (52.58%). ¹H-NMR (400 MHz, CDCl₃) δ: 4.34(1.91H), 4.07 (32.58H), 3.67 (1.76H), 3.41 (1.32H), 2.24-2.83 (42.88H),2.02 (3.03H), 1.67 (63.84H), 1.25 (3H). ¹³C-NMR (100 MHz, CDCl₃) δ:173.42, 70.36, 64.06, 60.54, 53.59, 44.11, 42.98, 41.58, 33.83, 28.21,25.25, 21.56, 14.33.

(5) Oxidation of VL/AVL Linear Polymer (80/20)

To a round bottom flask equipped with a stir bar, was added the VL/AVLpolymer (2.55 g; 3.87 mmol; 2.0 eq), m-CPBA (0.44 g; 2.15 mmol; 1.0 eq),and dichloromethane (47.2 mL; 5.4×10⁻² g/mL). The round bottom flask wasthen capped with a septum and allowed to stir for 72 h at roomtemperature. The resulting product solution was then concentrated andprecipitated into cold methanol. The methanol was decanted from theproduct, which was then transferred to a 6-dram vial usingdichloromethane. Yield: 835.6 mg (64.28%). ¹H-NMR (400 MHz, CDCl₃) δ:5.72 (1H), 5.04 (2.07H), 4.08 (41.05H), 3.66 (2.77H), 2.93 (0.84H), 2.75(0.95H), 2.29-2.53 (42.04), 1.69 (92.19H), 1.26 (2.15H). ¹³C-NMR (100MHz, CDCl₃) δ: 173.47, 135.26, 117.16, 64.97, 62.35, 60.49, 44.97,36.58, 33.83, 32.20, 28.19, 26.56, 21.58, 21.27, 14.38.

(6) Oxidation of VL/OPD/AVL Linear Polymer (60/20/20)

To a round bottom flask equipped with a stir bar, was added theVL/OPD/AVL polymer (0.35 g; 0.52 mmol; 2.0 eq), m-CPBA (51.89 mg; 0.26mmol; 1.0 eq), and dichloromethane (6.511 mL; 5.4×10⁻² g/mL). The roundbottom flask was then capped with a septum and allowed to stir for 72 hat room temperature. The resulting product solution was thenconcentrated and precipitated into cold methanol. The methanol wasdecanted from the product, which was then transferred to a 6-dram vialusing dichloromethane. Yield: 367 mg (84.95%). ¹H-NMR (400 MHz, CDCl₃)δ: 5.73 (1H), 5.05 (2.15H), 4.36 (4.29H), 4.11 (14.01H), 3.90 (2.04H),3.67 (5.04H), 3.43 (1.13H), 2.52-2.86 (21.18H), 2.16-2.52 (18.28H), 1.69(34.37H), 1.27 (1.59H). ¹³C-NMR (150 MHz, CDCl₃) δ: 169.68, 134.83,133.87, 131.26, 129.99, 128.42, 64.12, 53.60, 33.88, 28.24, 21.60.

5. Preparation of New Crosslinkers

(1) Preparation of Disulfide Linker

To a round bottom flask equipped with a stir bar, was added aldrithiol-2(10.00 g; 1.5 eq), 3-mercaptopropionic acid (3.212 g; 1.0 eq), and MeOH(excess). The yellow reaction was then allowed to stir for 72 h. Theresulting yellow solution was concentrated and the yellow product wasresuspended in dichloromethane and dried onto silica gel. The productwas then purified through column chromatography using a gradient of10%-30% ethyl acetate in hexanes to yield the pure, slightly off-whitesolid product. Yield: 2.23 g (34.17%). ¹H-NMR (400 MHz, CDCl₃) δ: 8.39(1H), 7.81 (2H), 7.22 (1H), 3.03 (2H), 2.71 (2H). ¹³C-NMR (100 MHz,CDCl₃) δ: 175.56, 159.39, 149.60, 137.64, 121.46, 120.85, 34.37, 34.24.

(2) Preparation of Disulfide Amine Crosslinker

To a round bottom flask equipped with a stir bar, in an ice bath, wasadded the previously synthesized disulfide linker (0.50 g; 2.32 mmol;6.0 eq), THF (excess), and triethylamine (0.33 g; 3.25 mmol; 8.4 eq),followed by the slow addition of isobutyl chloroformate (0.40 g; 2.90mmol; 7.5 eq). The reaction was then allowed to stir for 3 hours. To thestirring reaction mixture was then added pentaethylenhexamine (0.09 g;0.39 mmol; 1.0 eq) slowly drop wise. The reaction was then removed fromthe ice bath and allowed to run for an additional 24 hours at roomtemperature. The excess solvent was then removed on the rotovap toafford the crude, deep red product. The resulting crude product waspurified on the Biotage column system using a gradient of 2%-20% ethylacetate in hexanes to yield the pure, slightly off-white solid product.¹H-NMR (400 MHz, CDCl₃) δ: 8.42 (2H), 7.48 (2H), 7.18 (2.01H), 6.98(2.15H) 3.90 (4.56H), 3.45 (4.17H), 3.34 (1.16H), 2.89 (1.06H), 2.80(4.35), 1.13 (0.96H), 0.94 (15.11H). ¹³C-NMR (100 MHz, CDCl₃) δ: 172.33,158.41, 149.57, 136.17, 122.62, 119.65, 53.61, 42.93, 34.93, 27.88,25.18, 19.27.

6. Preparation of Nanoparticles

(1) Nanoparticle Formation Through Thiolene-Click Reactions UsingVL/OPD/AVL Copolymers (50 nm)

To a round bottom flask equipped with a stir bar, was added theVL/OPD/AVL polymer (111.5 mg; 5.431×10² mmol; 1 eq),3,6-dioxa-1,8-octanedithiol (9.90 mg; 5.431×10−2 mmol; 1 eq), anddichloromethane (16.76 mL; 3.24×10⁻³M). The flask was then fitted with areflux condenser and lowered into an oil bath at 45° C. to reflux for 12h. The resulting solution was then transferred to 10K dialysis tubingand dialyzed for 72 h against dichloromethane to remove any unreactedstarting material. The remaining product solution was then concentratedinto a preweighed vial and stored in the fridge. Yield: 81.8 mg(66.17%). ¹H-NMR (600 MHz, CDCl₃) δ: The significant change is thereduction of the allyl peaks at 5.72 and 5.04 ppm and the appearance ofsignals at 3.65 and 2.69 ppm corresponding to the protons neighboringthe thiols of the PEG linker after cross-linking. All other aspects ofthe spectrum remain similar to the polymer spectrum.

(2) Nanoparticle Formation Through Thiolene-Click Reactions UsingGLY/VL/AVL Copolymers (50 nm)

To a round bottom flask equipped with a stir bar, was added theGLY/VL/AVL polymer (118.75 mg; 2.74×10⁻² mmol; 1 eq),3,6-dioxa-1,8-octanedithiol (5.00 mg; 2.74×10⁻² mmol; 1 eq), andmethanol (8.47 mL; 3.24×10⁻³M). The flask was then fitted with a refluxcondenser and lowered into an oil bath at 45° C. to reflux for 12 h. Theresulting solution was then transferred to 10 K dialysis tubing anddialyzed for 72 h against dichloromethane to remove any unreactedstarting material. The remaining product solution was then concentratedinto a preweighed vial and stored in the fridge. Yield: 115.6 mg(93.41%). ¹H-NMR (600 MHz, CDCl₃) δ: The significant change is thereduction of the allyl peaks at 5.72 and 5.04 ppm and the appearance ofsignals at 3.65 and 2.69 ppm corresponding to the protons neighboringthe thiols of the PEG linker after cross-linking. All other aspects ofthe spectrum remain similar to the polymer spectrum.

(3) Nanoparticle Formation Through Thiolene-Click Reactions UsingGLY/AGE Copolymers (50 nm)

To a round bottom flask equipped with a stir bar, was added the GLY/AGEpolymer (111 mg; 1.79×10⁻¹ mmol; 2 eq), 3,6-dioxa-1,8-octanedithiol(16.35 mg; 8.97×10⁻² mmol; 1 eq), and methanol (55.36 mL; 3.24×10⁻³M).The flask was then fitted with a reflux condenser and lowered into anoil bath at 45° C. to reflux for 12 h. The resulting solution was thentransferred to 10K dialysis tubing and dialyzed for 72 h againstmethanol to remove any unreacted starting material. The remainingproduct solution was then concentrated into a preweighed vial and storedin the fridge. Yield: 103.1 mg (84.14%). ¹H-NMR (600 MHz, CDCl₃) δ: Thesignificant change is the reduction of the allyl peaks at 5.72 and 5.04ppm and the appearance of signals at 3.65 and 2.69 ppm corresponding tothe protons neighboring the thiols of the PEG linker aftercross-linking. All other aspects of the spectrum remain similar to thepolymer spectrum. FIG. 24 shows transmission electron microscopy (TEM)image for GLY/AGE nanoparticles with 3.5% crosslinking, after runningreaction for 12 hours in methanol at 45° C. FIG. 25 shows transmissionelectron microscopy (TEM) image for GLY/AGE nanoparticles with 7%crosslinking, after running reaction for 12 hours in methanol at 65° C.FIG. 26 shows transmission electron microscopy (TEM) image for GLY/AGEnanoparticles with 7% crosslinking, after running reaction for 12 hoursin methanol at 45° C.

(4) Nanoparticle Formation Through Thiolene-Click Reactions UsingGLY/GEA Copolymers (50 nm)

To a round bottom flask equipped with a stir bar, was added the GLY/GEApolymer (108.5 mg; 6.09×10⁻² mmol; 1 eq), 3,6-dioxa-1,8-octanedithiol(11.11 mg; 6.09×10⁻² mmol; 1 eq), and methanol (18.80 mL; 3.24×10⁻³M).The flask was then fitted with a reflux condenser and lowered into anoil bath at 45° C. to reflux for 12 h. The resulting solution was thentransferred to 10K dialysis tubing and dialyzed for 72 h againstmethanol to remove any unreacted starting material. The remainingproduct solution was then concentrated into a preweighed vial and storedin the fridge. Yield: 28.9 mg (23.92%). ¹H-NMR (600 MHz, CDCl₃) δ: Thesignificant change is the reduction of the allyl peaks at 5.72 and 5.04ppm and the appearance of signals at 3.65 and 2.69 ppm corresponding tothe protons neighboring the thiols of the PEG linker aftercross-linking. All other aspects of the spectrum remain similar to thepolymer spectrum.

(5) Nanoparticle Formation Through Amine-Epoxide Reactions UsingVL/AVL/EVL Copolymers

To a round bottom flask equipped with a stir bar, was added theVL/AVL/EVL polymer (30.1 mg; 2.45×10² mmol; 2 eq),2,2′-(Ethylenedioxy)bis-(ethylamine) (2.717 mg; 1.83×10⁻² mmol; 1.5 eq),and dichloromethane (7.54 mL; 3.24×10⁻³M). The flask was then fittedwith a reflux condenser and lowered into an oil bath at 45° C. to refluxfor 12 h. The resulting solution was then transferred to 10K dialysistubing and dialyzed for 72 h against dichloromethane to remove anyunreacted starting material. The remaining product solution was thenconcentrated into a preweighed vial and stored in the fridge. Yield:15.5 mg (47.4%). ¹H-NMR (600 MHz, CDCl₃) δ: The significant change isthe reduction of the allyl peaks at 2.96, 2.75, and 2.47 ppm and theappearance of signals at 3.5 and 2.89 ppm corresponding to the protonsneighboring the secondary amine of the PEG linker after cross-linking.All other aspects of the spectrum remain similar to the polymerspectrum.

(6) Nanoparticle Formation Through Amine-Epoxide Reactions UsingVL/AVL/EVL/OPD Copolymers

To a round bottom flask equipped with a stir bar, was added theVL/AVL/EVL/OPD polymer (83.6 mg; 5.67×10⁻² mmol; 2 eq),2,2′-(Ethylenedioxy)bis-(ethylamine) (6.30 mg; 4.25×10−2 mmol; 1.5 eq),and dichloromethane (17.49 mL; 3.24×10⁻³M). The flask was then fittedwith a reflux condenser and lowered into an oil bath at 45° C. to refluxfor 12 h. The resulting solution was then transferred to 10K dialysistubing and dialyzed for 72 h against dichloromethane to remove anyunreacted starting material. The remaining product solution was thenconcentrated into a preweighed vial and stored in the fridge. Yield:72.6 mg (79.06%). ¹H-NMR (600 MHz, CDCl₃) δ: The significant change isthe reduction of the allyl peaks at 2.96, 2.75, and 2.47 ppm and theappearance of signals at 3.5 and 2.89 ppm corresponding to the protonsneighboring the secondary amine of the PEG linker after cross-linking.All other aspects of the spectrum remain similar to the polymerspectrum.

7. Preparation of Combination of the Dual Two Component Drug DeliverySystem

a. General Procedure (for 17 Injections (20 μL Per Injection))

Bone morphogenetic protein (BMP2, 17 μL, 10 mg/mL in 20 mM acetic acid)was added to 159 mg polyglycidol. Nanoparticles containing MEK inhibitor(6.4% wt/wt) were dissolved in 244 μL sterile PBS to make 0.236 mg/mLsolution with respect to MEK inhibitor. Nanoparticle-MEK (4% crosslinkednanoparticle and 13% loading of inhibitor) inhibitor solution was addedto the polyglycidol and BMP2 mixture and sonicated to yield a viscous,but injectable solution (final polyglycidol concentration is 0.466 g/mL,each injection contains 10 μg BMP2 and 3.4 μg MEK inhibitor).

8. Preparation of Reconfigurable and Responsive Network Systems

(1) Non-Functionalized Polyglycidol-Based Crosslinking Materials forHydrogels: As Fillers in Hydrogels and as Component in Reconfigurableand Responsive Network Systems

A mixture of poly(MEC, MAC) (100 mg, M_(n)=4,700 g/mol, 0.10 mmolalkene), polyglycidol (100 mg, M_(n)=6,000 g/mol), and2,2-dimethoxy-2-phenylacetophenone (DMPA, 5.4 mg, 0.02 mmol) wasdissolved in DMF (0.10 mL) and allowed to stir at room temperature.3,6-dioxa-1,8-octane-dithiol (17 μL, 0.10 mmol) was added and reactionwas exposed to UV light (365 nm) for 5 minutes. The resulting gel waswashed in sequence with water, methanol, and dichloromethane and allowedto dry overnight in vacuo to yield a slightly opaque gel.

(2) Preparation of Polycarbonate/Polyglycidol Hydrogel Formation ViaThiolene Click and Zinc Acetate Rearrangement

A mixture of poly(MEC, MAC) (100 mg, Mn=4,700 g/mol, 0.10 mmol alkene),polyglycidol (100 mg, Mn=6,000 g/mol), and2,2-dimethoxy-2-phenylacetophenone (DMPA, 5.4 mg, 0.02 mmol) wasdissolved in DMF (0.10 mL) and allowed to stir at room temperature.3,6-dioxa-1,8-octane-dithiol (17 μL, 0.10 mmol) was added viamicrosyringe, followed by the addition of zinc acetate (5.8 mg, 0.03mmol). The reaction was exposed to UV light (365 nm) for 5 minutes. Theresulting gel was then placed in a 120° C. oil bath overnight. Theproduct washed in sequence with water, methanol, and dichloromethane andallowed to dry overnight in vacuo to yield a light yellow gel.

9. Preparation of Functionalized Polyglycidols

a. General Procedure

All reagents and solvents were commercial grade and purified prior touse when necessary. Tetrahydrofuran was dried by passage through acolumn of activated alumina as described by Grubbs (Pangborn, A. BOrganometallics 1996, 15, 1518-1520).

Dimethylformamide was distilled over CaH₂ and stored over molecularsieves. Glycidol was distilled under vacuum and stored over molecularsieves. Thin layer chromatography (TLC) was performed using glass-backedsilica gel (250 μm) plates and flash chromatography utilized 230-400mesh silica gel from Sorbent Technologies. Size exclusion chromatographywas utilized Sephadex LH-20 from Sigma Aldrich. UV light, and/or the useof CAM and potassium permanganate solutions were used to visualizeproducts.

Nuclear magnetic resonance spectra (NMR) were acquired on a BrukerDRX-500 (500 MHz), Bruker AV-400 (400 MHz) or Bruker AV II-600 (600 MHz)instrument. Chemical shifts are measured relative to residual solventpeaks as an internal standard set to δ 7.26 and δ 77.0 (CDCl₃), δ 3.31and δ 49.0 (CD₃OD). IR spectra were recorded on a Thermo Nicolet IR100spectrophotometer and are reported in wavenumbers (cm¹). Compounds wereanalyzed as neat films on a NaCl plate (transmission).

(1) Preparation of N-oxyphthalimide Polyglycidol Derivative

Polyglycidol was synthesized according to known literature procedure(Spears, B. R. Chem. Commun. 2013, 49, 2394-2396). To a 50 mL roundbottom flask fitted with an argon balloon and containing a solution ofpolyglycidol (M, =2-3 kDa, 2.0 g) in DMF (25 mL) was addedN-Hydroxyphthalimide (2.3 g, 14 mmol) followed by triphenylphosphine(3.7 g, 14 mmol) at rt. Diisopropylazodicarboxylate (2.7 mL, 14 mmol)was then added dropwise and the resulting mixture was stirred at rt for24 hrs. The reaction was concentrated under reduced pressure andprecipitated twice in ether:ethyl acetate (1:1) to obtain 2.6 g of thedesired polymer as an off-white solid. IR (film) 3455, 3061, 2919, 1789,1730, 1373, 1127, 731 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.74-7.48 (br m,4H), 3.06-4.49 (br m, 6H); ¹³C NMR (600 MHz, CDCl₃) ppm 162.8, 134.7,128.0, 123.4, 79.2, 77.8, 76.6, 74.9, 72.1, 71.4, 71.5-68.0 (broverlapping), 67.3, 65.2, 63.1, 61.2.

(2) Preparation of Aminooxy Polyglycidol Derivative

To a 50 mL round bottom flask equipped with a stir bar and an argonballoon was added a solution of N-oxyphthalimide polyglycidol (1.0 g) in1:1 mixture of methanol and dichloromethane (25 mL). A 10 fold excess(based on measurements from the synthesis of N-oxyphthalimidepolyglycidol) of anhydrous hydrazine (4.5 mL, 140 mmol) was added andthe reaction was allowed to stir for 12 hrs at rt. The reaction mixturewas filtered through 0.2 μm PTFE filter to remove the white solidbyproduct. Further purification by precipitation in ether followed bysize exclusion chromatography (sephadex LH-20 in methanol) yielded 800mg of the desired polymer. IR (film) 3407, 2873, 1373, 1113 cm⁻¹; ¹H NMR(600 MHz, CD₃OD) δ 3.50-4.49 (br m, 6H); ¹³C NMR (600 MHz, CD₃OD) ppm79.9, 79.4, 78.6, 77.7, 74.7, 72.6, 72.0, 71.9-70.4 (br overlappingpeaks), 70.0-68.8 (br, overlapping peaks), 66.2, 63.0, 61.9, 61.3.

As would be appreciated by those of skill, the percentage of theamino-oxy can be readily adjusted and has been done for other examples.

(3) Azide-Functionalized Polyglycidols and Allyl-FunctionalizedPolyglycidols

(A) Preparation of Alkyne Functionalization of Polyglycidol (Method 1)

A mixture of the appropriate propargyl bromide (1.00 equiv),polyglycidol secondary hydroxyl group (1.00 equiv), dried potassiumcarbonate (1.25 equiv), and 18-crown-6 (0.2 equiv) in DMF was heated at60° C. and stirred vigorously under nitrogen for 24 h. The mixture wasallowed to cool and add 50 mL methanol and then remove the solidcompound by vacuum filtration. The residue crude product wasprecipitated in vigorously stirred acetone, which was then decanted toafford the pure viscous product.

(b) Preparation of Alkyne Functionalization of Polyglycidol (Method 2)

A dry flask was charged with propargyl bromide (0.36 equiv),polyglycidol hydroxyl group (1.00 equiv), dried potassium hydroxidepellets (1.08 equiv) in DMSO was stirred vigorously under nitrogen atroom temperature for 12 h. The mixture was diluted with 50 mL methanoland the solid compound was removed by filtration. The residue crudeproduct was precipitated in vigorously stirred acetone, which was thendecanted to afford the pure viscous product. As would be appreciated bythose of skill, the percentage of the amount of the azide group can bereadily adjusted.

(4) Preparation of Glycidol-Alkyne-Azide

(A) Alkyne-Azide Click Reaction Catalyzed by Copper Foil

Polyglycidol-alkyne (0.11 g) was dissolved in 1 mL DMSO in a microwavevial. Benzyl azide (0.061 mL) and Cu foil (0.25 g) was added into thevial followed by irradiation at 160° C. for 15 min. After completion ofreaction, the reaction mixture was twice precipitated into acetone andsubsequently dried for 12 hours under vacuum. The product was obtainedas a highly viscous brown liquid. FIG. 30 shows the Click reaction viaNMR.

(5) Preparation of Random Copolyesters of Δ-valerolactone and2-oxepane-1,5-dione

To a 10 mL round bottom flask equipped with a stir bar and an argonballoon was added isoamyl alcohol (37 μL, 300 μmol) and tin(II)trifluoromethanesulfonate (1.3 mg, 3 mol). The mixture was stirred for10 min. In a vial, flamed dried under vacuum, was added2-oxepane-1,5-dione (242 mg, 1.89 mmol, synthesized according toliterature procedure (Van der Ende, A. E. J. Am Chem. Soc. 2008, 130,8706-13)), δ-valerolactone (702 μL, 7.57 mmol) and 2 mL ofN,N-dimethylformamide. Once all the 2-oxepane-1,5-dione had dissolved,the solution was added to the reaction in one portion, and stirred at rtfor 24 hrs. The reaction was then quenched with methanol andprecipitated from hexanes to give the desired golden brown polymer (806mg, 80%). M_(w)=1499 Da. ¹H NMR (400 MHz, CDCl₃) δ 4.42-4.24 (br m,—C(O)CH₂CH₂O—), 4.14-3.95 (br m, —CH₂CH₂CH₂O—), 2.82-2.67 (br m,—CH₂C(O)CH₂—), 2.63-2.46 (br m, —OC(O)CH₂CH₂C(O)—), 2.38-2.18 (br m,—OC(O)CH₂CH₂CH₂—), 1.91-1.79 (br m, (CH₃)₂CH—), 1.72-1.52 (br m,—C(O)CH₂CH₂CH₂CH₂O—), 1.52-1.42 (br m, (CH₃)₂CHCH₂—), 0.91-0.82 (br m,(CH₃)₂CH—).

(6) Preparation of 4-pentenoyl polyglycidol

To a flame dried 25 mL round bottom flask equipped with a stir bar andargon balloon was added polyglycidol (1 g) and pyridine (2 mL, 25 mmol).The reaction mixture was stirred at rt for 10 min then cooled to 0° C.Pentenoyl chloride (607 μL, 5.50 mmol) was added dropwise to thereaction. The reaction was allowed to warm up to rt and stirred for 12hrs. Reaction was then diluted with N,N-dimethylformamide (2 mL) andprecipitated in a mixture of diethyl ether and ethyl acetate (1:1) togive the desired product as a pale yellow oil (520 mg, 52%). ¹H NMR (400MHz, CD₃OD) δ 6.07-5.70 (br m, CH₂═CH—), 5.21-5.01 (br m, CH₂═CH—),4.96-4.50 (br s, —OH), 4.40-4.03 (br m, —CHCH₂OC(O)CH₂—), 4.02-3.86 (brm, —CHCH₂OH), 3.82-3.22 (br m, —OCHCH₂CHO—), 2.60-2.23 (br m,—C(O)CH₂CH₂CH═CH₂), 1.71-1.66 (br m, (CH₃)₂CH—), 1.50-1.39 (br m,(CH₃)₂CHCH₂—), 0.95-0.81 (br m, (CH₃)₂CH—). As would be appreciated bythose of skill, the amount and type of allyl group can be readilyadjusted.

(7) Preparation of 3-mercaptopropanoyl polyglycidol

To a 25 mL round bottom flask, flame dried and equipped with a stir barand argon balloon, was added a solution of polyglycidol (1 g) inN,N-dimethylformamide (1 mL), 3-mercaptopropionic acid (1.4 mL, 16.6mmol), and p-Toluenesulfonic acid (34 mg, 0.2 mmol). The mixture wasstirred at 100° C. for 24 hrs. The mixture was diluted withN,N-dimethylformamide (2 mL), and precipitated in ether. The product wasfurther purified by size exclusion chromatography (sephadex LH-20 inmethanol) to yield the desired polymer (200 mg). ¹H NMR (400 MHz, CD₃OD)δ 4.93 (br s, —OH), 4.46-4.08 (br m, —CHCH₂OC(O)CH₂—), 4.01-3.81 (br m,—CHCH₂OH), 3.85-3.41 (br m, —OCHCH₂CHO—), 2.81-2.63 (br m,—C(O)CH₂CH₂SH), 1.78-1.66 (br m, (CH₃)₂CH—), 1.52-1.42 (br m,(CH₃)₂CHCH₂—), 0.98-0.87 (br m, (CH₃)₂CH—). As would be appreciated bythose of skill, the amount and type of mercapto group can be readilyadjusted.

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What is claimed is:
 1. A method for making a polymer, the methodcomprising polymerizing glycidol in the presence of a tin catalyst toform the polymer, the polymer comprising at least one repeating unitformed from a monomer selected from:

or a combination thereof.
 2. The method of claim 1, wherein the tincatalyst is Sn(OTf)₂.
 3. The method of claim 1, further comprising thestep of crosslinking the polymer with crosslinks, wherein the crosslinkscomprise one or more of

wherein at least one of

is not
 0. 4. The method of claim 1, wherein polymerizing glycidol in thepresence of the tin catalyst is performed at a temperature of from −80°C. to 50° C.
 5. The method of claim 1, further comprising crosslinkingthe polymer.
 6. The method of claim 1, wherein the tin catalyst is a tin(II) catalyst.
 7. A method for making a polymer, the method comprisingpolymerizing glycidol in a presence of a tin catalyst to form thepolymer, the polymer comprising repeating units selected from:

wherein R⁰ is selected from H, alkyl, NH₂, and R¹; wherein R¹ comprisesa crosslinking functionality; wherein repeating units A1, A2, B1, and B2account for at least about 50 wgt % of the polymer; and wherein theratio of (A1+A2):(B1+B2) is greater than
 5. 8. The method of claim 7,wherein the tin catalyst is a tin (II) catalyst.
 9. The method of claim8, wherein the tin (II) catalyst is Sn(OTf)₂.
 10. The method of claim 7,wherein polymerizing glycidol in the presence of the tin catalyst isperformed at a temperature of from −80° C. to 50° C.
 11. A method offorming a nanoparticle comprising: polymerizing glycidol in a presenceof a tin catalyst to form a polymer, the polymer comprising at least onerepeating unit formed from a monomer selected from:

or a combination thereof; and crosslinking the polymer with crosslinks,wherein the crosslinks comprises

wherein at least one of

is not 0, thereby forming the nanoparticle.
 12. The method of claim 11,wherein the tin catalyst is a tin (II) catalyst.
 13. The method of claim12, wherein the tin (II) catalyst is Sn(OTf)₂.
 14. The method of claim11, wherein polymerizing glycidol in the presence of the tin catalyst isperformed at a temperature of from −80° C. to 50° C.